Table of Contents
REVIEW ARTICLE
Year : 2016  |  Volume : 1  |  Issue : 3  |  Page : 20-27

Role of the cathepsin K/Calcineurin/Nuclear factor of activated T-cells axis in the pathogenesis and management of diabetic cardiomyopathy


1 Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA
2 Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

Date of Web Publication26-Dec-2018

Correspondence Address:
Prof. Jun Ren
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071

Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2470-7511.248354

Get Permissions

  Abstract 


Diabetes mellitus has become a devastating global epidemic. Patients with diabetes suffer a high prevalence of diabetic cardiomyopathy (DCM). DCM is a type of cardiac problem independent of any preexisting macro- and micro-vascular diseases. The pathophysiological basis underlying diabetes-induced cardiac damage is rather complex and multifactorial. Although a number of risk factors including oxidative stress, apoptosis, and aberrant intracellular Ca2+ metabolism have been postulated to play a role in the onset and development of cardiac anomalies within diabetes, the precise mechanisms responsible for DCM remain elusive. This mini-review discusses the latest findings of mechanisms involved in the progression of cardiomyopathy in diabetes. We emphasize the role of the lysosomal cysteine protease, cathepsin K, and its downstream calcineurin/nuclear factor of activated T-cells signaling in the prevention and treatment of DCM.

Keywords: Calcineurin, cardiomyopathy, cathepsin K, diabetes, heart failure, nuclear factor of activated T-cells


How to cite this article:
Guo R, Nair S, Ren J. Role of the cathepsin K/Calcineurin/Nuclear factor of activated T-cells axis in the pathogenesis and management of diabetic cardiomyopathy. Cardiol Plus 2016;1:20-7

How to cite this URL:
Guo R, Nair S, Ren J. Role of the cathepsin K/Calcineurin/Nuclear factor of activated T-cells axis in the pathogenesis and management of diabetic cardiomyopathy. Cardiol Plus [serial online] 2016 [cited 2021 Oct 16];1:20-7. Available from: https://www.cardiologyplus.org/text.asp?2016/1/3/20/248354




  Introduction Top


Diabetes mellitus is a rapidly growing and chronic metabolic disease whose prevalence, alarmingly, is reaching epidemic proportions.[1] According to the Centers for Disease Control and Prevention, nearly 29.1 million people or 9.3% of the U.S. population were considered diabetic in 2012, thus imposing a major burden for health care. Ample clinical and experimental evidence has revealed that diabetes to be a major challenge for medical treatment; the disease ranks seventh in all-cause mortality in the United States. Furthermore, cardiovascular complications are the leading cause of mortality in patients with diabetes.[2],[3] The myopathic state in diabetes is manifested as ventricular dilation, cardiac remodeling, impaired ventricular contractility, ejection fraction and cardiac output, and increased risk for stroke and hypertension These complications eventually result in maladaption and heart failure.[4] Micro/macrovascular complications may also contribute to cardiac anomalies in diabetes.[5],[6] However, the pathological mechanisms leading to diabetic cardiomyopathy (DCM) remain poorly defined, particularly in the absence of coronary artery diseases. The current clinical strategy to reduce cardiovascular burden in patients with diabetes is mainly focused on controlling major metabolic abnormalities, such as hyperglycemia. Nonetheless, close monitoring of blood glucose levels has not been unequivocally successful in the management of cardiovascular events, in contrast to controlling other cardiovascular risk factors such as blood pressure, dyslipidemia, and platelet dysfunction.[2] Although a number of clinical studies are underway for the management of cardiovascular disease in diabetic subjects, clinical management of DCM has been somewhat dismal, warranting newer pharmacological strategies to surmount this problem. Recent evidence has revealed a possible role for proteases in diabetic complications.[7] Cathepsins belong to a group of lysosomal cysteine proteases that are ubiquitously expressed in various tissues with important roles in cancer and autoimmune and cardiovascular diseases.[8] Cathepsins are known to modulate protein turnover and apoptosis.[9] Cathepsin K, the most potent collagenase, is capable of regulating metabolism, adiposity, and glucose disposal, all of which play a major role in cardiac homeostasis.[10] Enhanced level and activity of cathepsin K have been reported in both patients and rodents with atherosclerosis,[11] neointimal lesions,[12] coronary artery disease,[13] hypertrophy, and heart failure.[14] Previous studies from our laboratory have shown that cathepsin K knockout attenuates high-fat-diet- and pressure overload-induced cardiac hypertrophy and contractile anomalies.[15],[16] This is consistent with the notion of a protective role of cathepsins in heart failure.[17] Although the protective effect of cathepsin K deletion is noted in cardiac function, possibly attributable to decreased protein synthesis via the inhibition of mTOR signaling,[15],[16] the precise role of cathepsin K and underlying mechanism in diabetic cardiovascular complications remains elusive.

Calcineurin/nuclear factor of activated T-cells (NFATs) signaling has been recently reported to regulate cardiac hypertrophy[18],[19] and promote the invasion of epicardium-derived cell into myocardium through regulation of extracellular matrix-degrading enzymes.[20] Calcineurin, a Ca2+/calmodulin (CaM)-dependent protein phosphatase, is reported to be upregulated in DCM.[18] Activation of calcineurin intensifies hypertrophic signals and accelerates the transition into the decompensatory state.[21] In rodent model, cardiac-specific activation of calcineurin or NFAT3 leads to cardiac hypertrophy which progresses rapidly to heart failure.[22] Calcineurin can also be directly cleaved by a Ca2+-dependent cysteine protease named calpain into its active form.[23] Based on this background and recent understanding of the mechanisms for the pathogenesis of DCM, it is plausible to postulate that cathepsin K deficiency may attenuate diabetic cardiovascular complications through calcineurin pathway. In addition, as a cysteine protease, cathepsin K, is likely to cleave calcineurin into an active form, subsequent activation of calcineurin/NFATs signaling may trigger diabetes-induced cardiac anomalies. Thus, targeting the calcineurin/NFATs signaling cascade downstream of cathepsin K may represent a novel strategy for prevention and/or treatment of DCM.


  Putative Mechanisms of Diabetic Cardiac Myopathy and Targets for Intervention Top


DCM, a disorder of the heart muscle in patients with diabetes, can lead to inefficient blood supply from the heart to the peripherals, a state known as heart failure.[24] However, the precise mechanisms underlying the disease are still controversial. Indeed, the pathogenesis of DCM is multifactorial. It is perceived that cardiac contractile dysfunction may be triggered by accelerated atherosclerosis and hypertension, with little evidence directly favoring an impact of diabetes mellitus on the alterations of myocardial structure and function independent of coronary artery disease, blood pressure, or valvular disease.[25] Based on our current understanding, the basic igniting mechanisms behind the complexities of DCM include metabolic disorder, insulin resistance, small vessel diseases, stimulation of renin-angiotensin-aldosterone system (RAAS), and increased cytokines. Besides, autophagy, cardiac autonomic neuropathy, miRNAs, and epigenetics may also contribute to the pathologic progress of DCM,[26],[27] as summarized in [Figure 1].
Figure 1: Proposed mechanisms contributing to the pathogenesis of diabetic cardiomyopathy. Blue boxes denote initiating mechanisms. Phrases by arrows indicate molecular and cellular mechanisms linking the respective initiating factors to the development of diabetic cardiomyopathy

Click here to view


Metabolic disturbances and altered insulin signaling

Metabolic perturbations such as hyperglycemia, hyperlipidemia, and hyperinsulinemia are the major factors causing damage to cardiomyocytes, fibroblast, endothelial cells, and small vessels, which contribute to the development of cardiomyopathy. Indeed, metabolic changes in diabetes are directly triggered by hyperglycemia which leads to altered glucose metabolism and glucotoxicity.[27] Direct and indirect glucotoxicity contributes to cardiac injury through multiple mechanisms, including oxidative stress, mitochondrial impairment, activated poly (ADP-ribose) polymerase-1, increased advanced glycation end-products (AGEs), and aldose reductase, the effects of which in turn induce cardiomyocyte apoptosis.[28] Increased AGEs and their receptors RAGEs activation is also associated with the activation of nuclear factor κB (NF-κB) signaling.[26] Hyperglycemia-induced higher reactive oxygen species (ROS) can activate matrix metalloproteinases 9 which contributes to increased matrix turnover, sarco-endoplasmic reticulum-calcium ATPase 2 (SERCA2) dysfunction, changes in miRNA, and enhanced inflammation.[29] In addition, hyperglycemia also causes enhanced endothelin-1 levels,[30] elevated hexosamine and polyol flux, activation of the classical isoforms of protein kinase C, altered cardiac structure through posttranslational modification of the extracellular matrix, and abnormalities in lipid metabolism as well as calcium ion homeostasis, via impaired ryanodine receptor (RyR), SERCA, and Na+-Ca2+ exchanger, thereby leading to decreased systolic and diastolic function.[28],[29] Hyperlipidemia can be induced by elevated free fatty acid (FFA) levels and disturbances of FFA metabolism that exceeds oxidation rates in the heart.[31] Enhanced accumulation of FFAs and triglycerides (TGs) in the myocardium leads to lipotoxicity which may induce inflammation and programmed myocardial cell death through ceramide production and ROS generation,[32] leading to mitochondrial dysfunction and ER stress, as well as decreases in both cardiolipin content and ATP synthesis.[26],[27],[28] Lipotoxicity-related DNA damage and altered small nuclear RNAs were also recently reported.[32],[33] Peroxisome proliferator-activated receptor-α/PGC-1(Peroxisome proliferator-activated receptor gamma coactivator 1) is another signaling network that controls fatty acid oxidation and plays an important role in regulating myocardial substrate use during diabetes.[34] Insulin resistance, concomitant with hyperinsulinemia, is another outcome of metabolic abnormities associating with the progression of both hypertrophic and dilated cardiomyopathy.[35] Both diabetic patients and diabetic animal models exhibit insulin resistance within the heart which is defined as diminished insulin-dependent stimulation of myocardial glucose uptake.[28] Previous studies suggested that nonesterified fatty acids play a critical role in triggering the pathogenesis of cellular insulin resistance and compensatory hyperinsulinemia.[36] Insulin resistance is related to the abnormalities of lipid and glucose metabolism, such as switching of cardiac substrate utilization from glucose to fatty acids.[37] In insulin resistance, hyperinsulinemia-induced dysregulation of cardiac substrate metabolism, altered myocardial insulin signaling, and altered progrowth pathways are considered associated with cardiac hypertrophy.[28],[38] There are at least four major cellular signaling cascades involved in hyperinsulinemia-associated cardiac hypertrophy. Generally, acute activation of (phosphoinositide 3-kinase α) PI3Kα/Akt-1 signaling phosphorylates and inactivates glycogen synthases kinase-3 β (GSK-3β), a well-recognized antagonist of the calcineurin action and inhibitor of nuclear transcription governing the hypertrophic process via the NFATs.[19] Higher insulin can also activate PI3K/PKB/Akt-1/mTOR pathway, which is involved in regulating cell growth and protein synthesis, and play an essential role in the development of physiological hypertrophy, whereas insulin-induced Akt-1-independent ERK/MAPK signaling, along with the PKC and calcineurin/NFAT pathways, mediates pathological hypertrophy.[28] FoxO transcription factor, downstream of Akt, also participates in cardiac remodeling. In addition, chronic hyperinsulinemia may activate Akt-1 indirectly by the enhanced activation of sympathetic nervous system (SNS)[39] or through triggering the angiotensin II (Ang II) pathway.[40]

Dysregulation of renin-angiotensin-aldosterone system

Activation of the SNS and RAAS has been reported in diabetes, leading to enhanced stimulation of both adrenergic and AT1 receptors, which contribute to myocardial remodeling and impairment of cardiac performance [summarized in [Figure 1]]. Increased Ang II has been demonstrated to be associated with cardiomyocyte hypertrophy, oxidative damage, apoptosis, and necrosis, which are related to cardiomyopathy in diabetic patients and rodent model.[41],[42] Moreover, upregulated Ang II and aldosterone during diabetes are able to induce cardiac fibrosis and stiffness, which is characterized by enhanced accumulation of collagen and increased proliferation of cardiac fibroblasts, leading to cardiac microvasculature alterations and hypertrophy in diabetic subjects.[43] Ang II also exhibits the effects on the insulin receptor and Insulin receptorsubstrate proteins (IRS proteins) and the downstream effectors such as PI3K, Akt, and glucose transporter 4 (GLUT4). Thus, diabetes-associated cardiovascular anomalies are prevented by pharmacological inhibition of RAAS, such as aldosterone antagonist spironolactone, angiotensin receptor blockers, and (ACE) Angiotensin-converting enzyme inhibitors.[26],[28],[44],[45] Furthermore, activation of RAAS further altered insulin/insulin-like growth factor-1 (IGF-1) signaling pathway which is detrimental to both cardiomyocytes and endothelial cells.[46] IGF-1 is a pivotal factor for cardiac growth and function and is able to modulate Ang II. It has been shown that IGF-1 was reduced in diabetes, and exogenous IGF-I intervention attenuated cardiomyocyte contractile disturbances in diabetic animals, indicating an important role of IGF-I in cardiac fibrosis and DCM progression.[27]

Activation of cytokines

Increased cytokines, contributing to the induction of inflammation and fibrosis of the heart and endothelial cells, were also observed in DCM. Increased collagen deposition and fibrous tissue formation may be related to increased expression of (TGF-β) transforming growth factor-β during tissue repair by binding to the TGF-β type II receptor.[47] In addition, increased expression of cell adhesion molecules (ICAM-1 and vascular cell adhesion molecule 1), increased infiltration of macrophages and leukocytes, and increased expression of other inflammatory cytokines (interleukin [IL]-1 β, IL-6, IL-18, and tumor necrosis factor [TNF]-α) were also demonstrated in DCM relating to intramyocardial inflammation.[26] Anti-TNF-α treatment and inhibition of IL-converting enzyme have been shown to display beneficial effects for reducing inflammation in the heart.[48],[49] Besides, adipocytes also synthesize and secrete a number of cytokines (adipokines) that play significant roles in type II diabetes and insulin resistance. There is growing evidence suggesting that the adipokines such as leptin, adiponectin, and apelin exert protective role in the heart from lipotoxicity, calcium disorder, endothelial dysfunction, and cardiac remodeling. However, resistin displayed a detrimental effect on cardiac function through alterations in cardiac metabolism and induction of myocardial insulin resistance.[28] Therefore, alterations in adipokines may contribute to the development of DCM.

Small vessel diseases and other factors

Structural and functional abnormalities of small vessels in diabetic heart may also contribute to the pathogenesis of heart failure although this hypothesis remains controversial. Atherosclerosis is the major threat to the macrovasculature, while small vessel damage is typically related to microvasculature, including arterioles, capillaries, and venules, where a variety of cellular and molecular mechanisms involved in the process of DCM. Endothelium-dependent dilation of coronary microvasculature was found impaired in dilated cardiomyopathy.[50] As an independent mechanism, autonomic nervous system also contributes to the development of DCM by altering myocardial blood flow. In fact, microcirculation is under the regulation of autonomic sympathetic nerves, parasympathetic nerves, and the substances produced by the endothelial cells and metabolic local products.[27] Beyond what is mentioned above, epigenetics, impaired autophagy, changing miRNA levels (e.g., miR-15a, miR-30d, miR-143, and miR-181) may also contribute to DCM.[26] In addition, among all of the effects generated from those triggering mechanisms, oxidative stress and calcineurin/NFATs signaling cascade are currently recognized as the major contributors for the pathogenesis of DCM.[27]


  Role of Cathepsins in Cardiomyopathy and Heart Failure Top


Proteases, as proteolytic enzymes, contribute to protein degradation and thereby are partially responsible for cardiovascular dysfunction. Alterations of proteolytic activities are always observed in both the extra- and the intra-cellular environment in heart failure and are correlated with hypertrophic cardiomyopathy and dilated cardiomyopathy such as DCM.[51] Cathepsins belong to a family of lysosomal proteases and are involved in the turnover of proteins delivered to the lysosome.[52] Several cathepsins such as cathepsin L, B, and S were showed to be capable of regulating autophagy.[53],[54],[55] They have also been noted contribute to cardiovascular dysfunction in heart disease and involve a number of biological process, including antigen presentation, extracellular matrix (ECM) turnover, neuropeptide and hormone processing, and promoting inflammation and apoptosis.[8],[9] Cathepsins are generally active within lysosomes and are active within a specific pH range; however, compromised lysosomal integrity leads to leakage of cathepsins to the cytosol and subsequent degradation of cellular components.[56] Previous studies have shown that the expression and activity of a series of cathepsins involving cathepsin S, B, D, and K were increased in hypertrophic and failing heart.[9],[57],[58] In contrast, deletion of cathepsin L exhibits dilated cardiomyopathy, and overexpression of cathepsin L in mouse model alleviates cardiac inflammation, fibrosis, and hypertrophy.[59] These studies strongly suggest a role for cathepsins in heart failure.

Cathepsin K, the most potent mammalian cathepsin, is a lysosomal cysteine protease that is predominantly expressed in osteoclasts and has been found to mediate bone degradation attributable to a strong elastase and collagenase properties.[60] Recently, a growing number of evidence showing that cathepsin K exhibits a negative effect on glucose and lipid metabolism; conversely, inhibition of cathepsin K attenuated body weight gain and elevated serum glucose and insulin levels in obese mice.[10],[61],[62] In addition, expression and activity of cathepsin K were elevated in both patients and animals with atherosclerosis, neointimal lesions, coronary artery disease, hypertrophy, and heart failure.[11],[12],[13],[14] Our recent studies have shown that cathepsin K protein levels were dramatically elevated in the human myocardium of end-stage dilated cardiomyopathy and deletion of cathepsin K protected against cardiac dysfunctions.[15],[16] We also found that cathepsin K knockout has a distinct improvement in whole-body glucose utilization.[16] Although there are increasing numbers of studies on cathepsin K, the majority of them focus on bone and there is limited research focusing on the role of cathepsin K in heart disease. Furthermore, the potential cellular and molecular mechanism by which cathepsin K is involved in the pathophysiology of cardiac function and developing DCM is yet unclear.


  Calcineurin/Nuclear Factor of Activated T-Cells Signaling in Cardiomyopathy and Heart Failure Top


As one of the potential mechanisms in the pathogenesis of DCM, calcineurin plays an essential role in transducing hypertrophic signals in part by NFAT transcription factors.[63] Molkentin found that the activation of calcineurin was sufficient to induce cardiac hypertrophy contributing to dilated cardiomyopathy and heart failure and eventually cause sudden death.[22] Inhibition of calcineurin activity or calcineurin/NFATs signaling restrains the induction of brain natriuretic peptide and cardiomyocyte hypertrophy.[18],[64]

Calcineurin, a eukaryotic ubiquitously expressed serine/threonine-protein phosphatase, is activated by calmodulin upon increased intracellular calcium. Abundant evidence supports that calcineurin participates in a number of cellular processes including Ca2+-dependent signal transduction pathways. In skeletal muscle, the expression of fiber type-specific gene can be regulated by calcineurin, which is dependent on contractile activity and Ca2+ signaling.[65],[66] Calcineurin is able to modulate the activities of L-type Ca2+ channel, ryanodine receptor (RyR)/Ca2+-release channels,[67],[68] the inositol 1, 4, 5-triphosphate receptor,[69] and SERCA 2a,[70] thus influence Ca2+ fluxes,[71] in the heart. Indeed, Ca2+ is known as an essential signal for myocardial remodeling and the process of cardiac hypertrophy. The disturbance of Ca2+ homeostasis can cause cardiomyocyte-contractile dysfunction and play a vital role in the pathophysiology of heart failure. Our studies showed that calcineurin inhibitor cyclosporine A alleviated high glucose-induced attenuation of SERCA2 protein, indicating that Ca2+ channel proteins can be modulated by calcineurin. Nevertheless, evidence also suggested that cardiac hypertrophy and heart failure can be induced by the reduction of L-type Ca2+ channel activity through activation of calcineurin/NFAT signaling in mice.[72] Taken together, a mutual effect may exist between calcineurin and Ca2+ channels. Further studies are necessary to determine the upstream or downstream signals, leading the cardiac hypertrophy under the aforementioned conditions.

Furthermore, activation of calcineurin dephosphorylates the regulatory domains of NFATs within the cytoplasm, and dephosphorylated NFATs translocate to the nucleus for gene transcription in cooperation with other transcription factors.[19] According to Fiedler et al.[64] and Gao et al.,[73] NFAT activation can also be triggered by the current of L-type Ca2+-channel. Four calcineurin-regulated NFAT transcriptional factors including NFATc1-c4 are present in the myocardium.[74] Recently, NFATc3 and NFATc4 (NFAT3) have been shown as downstream targets of calcineurin and are associated with hypertrophic response.[75] NFATc4 can stimulate the transcription of pro-hypertrophic genes including MEF2 and GATA4, leading to pathological hypertrophy.[76] NFATc1 has been considered as an necessary factor for endocardial valve remodeling, formation of coronary vessels and fibrous matrix in the mature heart, and an essential effector of receptor activator of NF-κB ligand signaling, which required for cathepsin K expression.[20],[77] Research also indicated that NFATs may interact with NF-κB/p65 and activate NFκB through its nuclear translocation in cardiomyocytes. Genetic deletion of calcineurin/NFATs displayed compromised NF-κB transcriptional activation, which is required for pressure overload-induced cardiac hypertrophy. On the other side, intact NF-κB signaling and p65 transcriptional activity are required for entire transcriptional activation of NFATs.[78] In addition, the association of NFATs and NF-κB with cardiomyocyte apoptosis was also reported.[79],[80]


  Crosstalk between Cathepsin K and Calcineurin in Diabetic Cardiomyopathy Top


Because cathepsin K and calcineurin/NFATs signaling pathway both have been involved in the regulation of cardiac hypertrophy, we propose that there is a crosstalk between these two previously deemed independent signaling pathways. Three suppositions are posted in this review. In the first place, cathepsin K is capable of dysregulating glucose metabolism and increasing glucotoxicity, which can trigger calcineurin/NFATs signaling. This is according to the evidence that hyperinsulinemia and hyperglycemia can trigger calcineurin-NFATs pathway.[19],[28],[81],[82] In our experimental diabetic model, streptozotocin (STZ) injections induced higher level of cathepsin K in murine heart, while cathepsin K knockout significantly attenuated STZ-induced increased fasting blood glucose level and calcineurin A expression in mouse heart. In addition, STZ-induced ventricular dilation and cardiac dysfunction were markedly alleviated by cathepsin K deletion. Since β-cells are destroyed in STZ-treated animal model, hyperglycemia, and glucotoxicity, rather than that hyperinsulinemia after STZ challenge possibly triggers dilated cardiomyopathy and cardiac dysfunction through upregulation of cathepsin K. Second, high cathepsin K level may induce cardiac anomalies by dysregulation of calcium homeostasis, which triggers calcineurin activation. Our studies (unpublished) showed that deletion of cathepsin K dramatically reversed STZ-induced reduction in SERCA2 and phospholamban phosphorylation at Ser16 and Thr17. STZ-induced elevation of intracellular calcium concentration was also attenuated by cathepsin K knockout. These results indicate that cathepsin K maybe acts as an upstream signal for regulating Ca2+ flux that contributes to calcineurin activation. Most interestingly, we postulate that cathepsin K, as a cysteine protease, is likely to cleave calcineurin into an active form or inhibit calcineurin from auto-inhibition, which in turn stimulates NFATs translocation and subsequently triggers diabetes-induced cardiac dysfunctions and cardiomyopathy [summarized in [Figure 2]]. Glucose toxicity in diabetes contributes to DCM via upregulated cathepsin K and calcineurin/NFAT signaling, which plays an important role in cardiac remodeling and hypertrophy in diabetes.
Figure 2: Diagram showing the role of cathepsin K and calcineurin in diabetic cardiomyopathy. Glucose toxicity in diabetes contributes to diabetic cardiomyopathy via upregulated cathepsin K and calcineurin/nuclear factor of activated T-cells signaling, which plays an important role in cardiac remodeling and hypertrophy in diabetes. Targeting cathepsin K may represent an attractive strategy to treat or prevent diabetes-associated cardiac complications

Click here to view


Targeting cathepsin K may represent an attractive strategy to treat or prevent diabetes-associated cardiac complications. Previous evidence suggests that calpain, a Ca2+-dependent cysteine protease, can directly cleave calcineurin into active form both in vitro and in vivo.[23] Therefore, there would be a possible physical interaction between cathepsin K and calcineurin. Future work needs to be done to explore the specific cleavage sites of cathepsin K and structural basis for the activation of calcineurin.


  Summary and Perspectives Top


Diabetes is an independent risk factor for cardiovascular disease, which is the leading cause of mortality and morbidity in our society. In addition to increasing risk of coronary artery disease and hypertension, a growing amount of evidence suggested that diabetic patients are also prone to a condition termed as DCM, which is characterized by structural and functional changes of the heart muscle, such as increased fibrosis, cardiac hypertrophy, and diastolic impairments. Currently, there is an increased understanding of the cellular and molecular mechanisms in diabetes, including metabolic perturbations, insulin resistance, myocardial fibrosis, cardiac autonomic neuropathy, increased oxidative stress and ER stress, impaired autophagy, changes in miRNA levels and affected epigenetics, all of which contribute to the pathogenesis of DCM. Therein, calcineurin/NFATs signaling cascade is thought as an essential contributor during the process of cardiomyopathy. Despite the numerous drugs present in the market for prevention and treatment targeting on improving glycemic control and ameliorating cardiovascular dysfunction for diabetic patients, the incidence of diabetes-associated cardiovascular disease continues to rise. Cathepsin K, an important cysteine protease, plays a vital role in the development of cardiomyopathy. It is hoped that targeting cathepsin K will generate a novel therapy tailored to reduce the risk of heart failure in individuals with diabetes mellitus, although the specific mechanism still remains elusive. Further study of understanding the mechanisms between cathepsin K and calcineurin needs to tested and clarified.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Tabish SA. Is diabetes becoming the biggest epidemic of the twenty-first century? Int J Health Sci (Qassim) 2007;1:V-VIII.  Back to cited text no. 1
    
2.
Lathief S, Inzucchi SE. Approach to diabetes management in patients with CVD. Trends Cardiovasc Med 2016;26:165-79.  Back to cited text no. 2
    
3.
Diabetes mellitus: A major risk factor for cardiovascular disease. A joint editorial statement by the American Diabetes Association; the National Heart, Lung, and Blood Institute; the Juvenile Diabetes Foundation International; the National Institute of Diabetes and Digestive and Kidney Diseases; and the American Heart Association. Circulation 1999;100:1132-3.  Back to cited text no. 3
    
4.
Fein FS. Diabetic cardiomyopathy. Diabetes Care 1990;13:1169-79.  Back to cited text no. 4
    
5.
Gore MO, McGuire DK. Cardiovascular disease and type 2 diabetes mellitus: Regulating glucose and regulating drugs. Curr Cardiol Rep 2009;11:258-63.  Back to cited text no. 5
    
6.
Norby FL, Aberle NS 2nd, Kajstura J, Anversa P, Ren J. Transgenic overexpression of insulin-like growth factor I prevents streptozotocin-induced cardiac contractile dysfunction and beta-adrenergic response in ventricular myocytes. J Endocrinol 2004;180:175-82.  Back to cited text no. 6
    
7.
Zhang Z, Wu X, Cai T, Gao W, Zhou X, Zhao J, et al. Matrix metalloproteinase 9 gene promoter (rs 3918242) mutation reduces the risk of diabetic microvascular complications. Int J Environ Res Public Health 2015;12:8023-33.  Back to cited text no. 7
    
8.
Reiser J, Adair B, Reinheckel T. Specialized roles for cysteine cathepsins in health and disease. J Clin Invest 2010;120:3421-31.  Back to cited text no. 8
    
9.
Lutgens SP, Cleutjens KB, Daemen MJ, Heeneman S. Cathepsin cysteine proteases in cardiovascular disease. FASEB J 2007;21:3029-41.  Back to cited text no. 9
    
10.
Yang M, Sun J, Zhang T, Liu J, Zhang J, Shi MA, et al. Deficiency and inhibition of cathepsin K reduce body weight gain and increase glucose metabolism in mice. Arterioscler Thromb Vasc Biol 2008;28:2202-8.  Back to cited text no. 10
    
11.
Hofnagel O, Robenek H. Cathepsin K: Boon or bale for atherosclerotic plaque stability? Cardiovasc Res 2009;81:242-3.  Back to cited text no. 11
    
12.
Hu L, Cheng XW, Song H, Inoue A, Jiang H, Li X, et al. Cathepsin K activity controls injury-related vascular repair in mice. Hypertension 2014;63:607-15.  Back to cited text no. 12
    
13.
Cheng XW, Kikuchi R, Ishii H, Yoshikawa D, Hu L, Takahashi R, et al. Circulating cathepsin K as a potential novel biomarker of coronary artery disease. Atherosclerosis 2013;228:211-6.  Back to cited text no. 13
    
14.
Zhao G, Li Y, Cui L, Li X, Jin Z, Han X, et al. Increased circulating cathepsin K in patients with chronic heart failure. PLoS One 2015;10:e0136093.  Back to cited text no. 14
    
15.
Hua Y, Xu X, Shi GP, Chicco AJ, Ren J, Nair S, et al. Cathepsin K knockout alleviates pressure overload-induced cardiac hypertrophy. Hypertension 2013;61:1184-92.  Back to cited text no. 15
    
16.
Hua Y, Zhang Y, Dolence J, Shi GP, Ren J, Nair S, et al. Cathepsin K knockout mitigates high-fat diet-induced cardiac hypertrophy and contractile dysfunction. Diabetes 2013;62:498-509.  Back to cited text no. 16
    
17.
Müller AL, Dhalla NS. Role of various proteases in cardiac remodeling and progression of heart failure. Heart Fail Rev 2012;17:395-409.  Back to cited text no. 17
    
18.
Sussman MA, Lim HW, Gude N, Taigen T, Olson EN, Robbins J, et al. Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science 1998;281:1690-3.  Back to cited text no. 18
    
19.
Molkentin JD. Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc Res 2004;63:467-75.  Back to cited text no. 19
    
20.
Combs MD, Braitsch CM, Lange AW, James JF, Yutzey KE. NFATC1 promotes epicardium-derived cell invasion into myocardium. Development 2011;138:1747-57.  Back to cited text no. 20
    
21.
Harvey PA, Leinwand LA. The cell biology of disease: Cellular mechanisms of cardiomyopathy. J Cell Biol 2011;194:355-65.  Back to cited text no. 21
    
22.
Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, et al. Acalcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 1998;93:215-28.  Back to cited text no. 22
    
23.
Wu HY, Tomizawa K, Oda Y, Wei FY, Lu YF, Matsushita M, et al. Critical role of calpain-mediated cleavage of calcineurin in excitotoxic neurodegeneration. J Biol Chem 2004;279:4929-40.  Back to cited text no. 23
    
24.
Liu Q, Wang S, Cai L. Diabetic cardiomyopathy and its mechanisms: Role of oxidative stress and damage. J Diabetes Investig 2014;5:623-34.  Back to cited text no. 24
    
25.
Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A, et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972;30:595-602.  Back to cited text no. 25
    
26.
Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 2014;57:660-71.  Back to cited text no. 26
    
27.
Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: Evidence, mechanisms, and therapeutic implications. Endocr Rev 2004;25:543-67.  Back to cited text no. 27
    
28.
Battiprolu PK, Gillette TG, Wang ZV, Lavandero S, Hill JA. Diabetic cardiomyopathy: Mechanisms and therapeutic targets. Drug Discov Today Dis Mech 2010;7:e135-43.  Back to cited text no. 28
    
29.
Chavali V, Tyagi SC, Mishra PK. Predictors and prevention of diabetic cardiomyopathy. Diabetes Metab Syndr Obes 2013;6:151-60.  Back to cited text no. 29
    
30.
Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic cardiomyopathy: Mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther 2014;142:375-415.  Back to cited text no. 30
    
31.
Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K, et al. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J 2004;18:1692-700.  Back to cited text no. 31
    
32.
van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P. Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc Res 2011;92:10-8.  Back to cited text no. 32
    
33.
Michel CI, Holley CL, Scruggs BS, Sidhu R, Brookheart RT, Listenberger LL, et al. Small nucleolar RNAs U32a, U33, and U35a are critical mediators of metabolic stress. Cell Metab 2011;14:33-44.  Back to cited text no. 33
    
34.
An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 2006;291:H1489-506.  Back to cited text no. 34
    
35.
Witteles RM, Fowler MB. Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options. J Am Coll Cardiol 2008;51:93-102.  Back to cited text no. 35
    
36.
Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: The search for a unifying hypothesis. Circ Res 2006;98:596-605.  Back to cited text no. 36
    
37.
Belke DD, Betuing S, Tuttle MJ, Graveleau C, Young ME, Pham M, et al. Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin Invest 2002;109:629-39.  Back to cited text no. 37
    
38.
Paternostro G, Pagano D, Gnecchi-Ruscone T, Bonser RS, Camici PG. Insulin resistance in patients with cardiac hypertrophy. Cardiovasc Res 1999;42:246-53.  Back to cited text no. 38
    
39.
Morisco C, Condorelli G, Trimarco V, Bellis A, Marrone C, Condorelli G, et al. Akt mediates the cross-talk between beta-adrenergic and insulin receptors in neonatal cardiomyocytes. Circ Res 2005;96:180-8.  Back to cited text no. 39
    
40.
Samuelsson AM, Bollano E, Mobini R, Larsson BM, Omerovic E, Fu M, et al. Hyperinsulinemia: Effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways. Am J Physiol Heart Circ Physiol 2006;291:H787-96.  Back to cited text no. 40
    
41.
Kajstura J, Fiordaliso F, Andreoli AM, Li B, Chimenti S, Medow MS, et al. IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes 2001;50:1414-24.  Back to cited text no. 41
    
42.
Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, et al. Myocardial cell death in human diabetes. Circ Res 2000;87:1123-32.  Back to cited text no. 42
    
43.
Hayat SA, Patel B, Khattar RS, Malik RA. Diabetic cardiomyopathy: Mechanisms, diagnosis and treatment. Clin Sci (Lond) 2004;107:539-57.  Back to cited text no. 43
    
44.
Singh VP, Le B, Khode R, Baker KM, Kumar R. Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis. Diabetes 2008;57:3297-306.  Back to cited text no. 44
    
45.
Brown L, Wall D, Marchant C, Sernia C. Tissue-specific changes in angiotensin II receptors in streptozotocin-diabetic rats. J Endocrinol 1997;154:355-62.  Back to cited text no. 45
    
46.
Cooper SA, Whaley-Connell A, Habibi J, Wei Y, Lastra G, Manrique C, et al. Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance. Am J Physiol Heart Circ Physiol 2007;293:H2009-23.  Back to cited text no. 46
    
47.
Mizushige K, Yao L, Noma T, Kiyomoto H, Yu Y, Hosomi N, et al. Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model. Circulation 2000;101:899-907.  Back to cited text no. 47
    
48.
Westermann D, Van Linthout S, Dhayat S, Dhayat N, Escher F, Bücker-Gärtner C, et al. Cardioprotective and anti-inflammatory effects of interleukin converting enzyme inhibition in experimental diabetic cardiomyopathy. Diabetes 2007;56:1834-41.  Back to cited text no. 48
    
49.
Westermann D, Van Linthout S, Dhayat S, Dhayat N, Schmidt A, Noutsias M, et al. Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol 2007;102:500-7.  Back to cited text no. 49
    
50.
Treasure CB, Vita JA, Cox DA, Fish RD, Gordon JB, Mudge GH, et al. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation 1990;81:772-9.  Back to cited text no. 50
    
51.
Müller AL, Freed D, Hryshko L, Dhalla NS. Implications of protease activation in cardiac dysfunction and development of genetic cardiomyopathy in hamsters. Can J Physiol Pharmacol 2012;90:995-1004.  Back to cited text no. 51
    
52.
Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, et al. Cysteine cathepsins: From structure, function and regulation to new frontiers. Biochim Biophys Acta 2012;1824:68-88.  Back to cited text no. 52
    
53.
Goldspink DF, Lewis SE, Kelly FJ. Protein turnover and cathepsin B activity in several individual tissues of foetal and senescent rats. Comp Biochem Physiol B 1985;82:849-53.  Back to cited text no. 53
    
54.
Hsu KF, Wu CL, Huang SC, Wu CM, Hsiao JR, Yo YT, et al. Cathepsin L mediates resveratrol-induced autophagy and apoptotic cell death in cervical cancer cells. Autophagy 2009;5:451-60.  Back to cited text no. 54
    
55.
Huang CC, Chen KL, Cheung CH, Chang JY. Autophagy induced by cathepsin S inhibition induces early ROS production, oxidative DNA damage, and cell death via xanthine oxidase. Free Radic Biol Med 2013;65:1473-86.  Back to cited text no. 55
    
56.
Turk B, Stoka V. Protease signalling in cell death: Caspases versus cysteine cathepsins. FEBS Lett 2007;581:2761-7.  Back to cited text no. 56
    
57.
Cheng XW, Obata K, Kuzuya M, Izawa H, Nakamura K, Asai E, et al. Elastolytic cathepsin induction/activation system exists in myocardium and is upregulated in hypertensive heart failure. Hypertension 2006;48:979-87.  Back to cited text no. 57
    
58.
Yamac AH, Sevgili E, Kucukbuzcu S, Nasifov M, Ismailoglu Z, Kilic E, et al. Role of cathepsin D activation in major adverse cardiovascular events and new-onset heart failure after STEMI. Herz 2015;40:912-20.  Back to cited text no. 58
    
59.
Tang Q, Cai J, Shen D, Bian Z, Yan L, Wang YX, et al. Lysosomal cysteine peptidase cathepsin L protects against cardiac hypertrophy through blocking AKT/GSK3beta signaling. J Mol Med (Berl) 2009;87:249-60.  Back to cited text no. 59
    
60.
Lotinun S, Kiviranta R, Matsubara T, Alzate JA, Neff L, Lüth A, et al. Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J Clin Invest 2013;123:666-81.  Back to cited text no. 60
    
61.
Funicello M, Novelli M, Ragni M, Vottari T, Cocuzza C, Soriano-Lopez J, et al. Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores. PLoS One 2007;2:e683.  Back to cited text no. 61
    
62.
Chiellini C, Costa M, Novelli SE, Amri EZ, Benzi L, Bertacca A, et al. Identification of cathepsin K as a novel marker of adiposity in white adipose tissue. J Cell Physiol 2003;195:309-21.  Back to cited text no. 62
    
63.
Gruver CL, DeMayo F, Goldstein MA, Means AR. Targeted developmental overexpression of calmodulin induces proliferative and hypertrophic growth of cardiomyocytes in transgenic mice. Endocrinology 1993;133:376-88.  Back to cited text no. 63
    
64.
Fiedler B, Lohmann SM, Smolenski A, Linnemuller S, Pieske B, Schroder F, et al. Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes. Proc Natl Acad Sci U S A 2002;99:11363-8.  Back to cited text no. 64
    
65.
Schulz RA, Yutzey KE. Calcineurin signaling and NFAT activation in cardiovascular and skeletal muscle development. Dev Biol 2004;266:1-6.  Back to cited text no. 65
    
66.
Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, Shelton JM, et al. Acalcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev 1998;12:2499-509.  Back to cited text no. 66
    
67.
Bandyopadhyay A, Shin DW, Ahn JO, Kim DH. Calcineurin regulates ryanodine receptor/Ca(2+)-release channels in rat heart. Biochem J 2000;352 Pt 1:61-70.  Back to cited text no. 67
    
68.
Xiao RP, Valdivia HH, Bogdanov K, Valdivia C, Lakatta EG, Cheng H, et al. The immunophilin FK506-binding protein modulates ca2+release channel closure in rat heart. J Physiol 1997;500 (Pt 2):343-54.  Back to cited text no. 68
    
69.
Cameron AM, Steiner JP, Roskams AJ, Ali SM, Ronnett GV, Snyder SH, et al. Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates ca2+ flux. Cell 1995;83:463-72.  Back to cited text no. 69
    
70.
Münch G, Bölck B, Karczewski P, Schwinger RH. Evidence for calcineurin-mediated regulation of SERCA 2a activity in human myocardium. J Mol Cell Cardiol 2002;34:321-34.  Back to cited text no. 70
    
71.
Matthes J, Jäger A, Handrock R, Groner F, Mehlhorn U, Schwinger RH, et al. Ca2+-dependent modulation of single human cardiac L-type calcium channels by the calcineurin inhibitor cyclosporine. J Mol Cell Cardiol 2004;36:241-55.  Back to cited text no. 71
    
72.
Goonasekera SA, Hammer K, Auger-Messier M, Bodi I, Chen X, Zhang H, et al. Decreased cardiac L-type ca2+ channel activity induces hypertrophy and heart failure in mice. J Clin Invest 2012;122:280-90.  Back to cited text no. 72
    
73.
Gao H, Wang F, Wang W, Makarewich CA, Zhang H, Kubo H, et al. Ca(2+) influx through L-type Ca(2+) channels and transient receptor potential channels activates pathological hypertrophy signaling. J Mol Cell Cardiol 2012;53:657-67.  Back to cited text no. 73
    
74.
Wilkins BJ, De Windt LJ, Bueno OF, Braz JC, Glascock BJ, Kimball TF, et al. Targeted disruption of NFATc3, but not NFATc4, reveals an intrinsic defect in calcineurin-mediated cardiac hypertrophic growth. Mol Cell Biol 2002;22:7603-13.  Back to cited text no. 74
    
75.
Olson EN, Molkentin JD. Prevention of cardiac hypertrophy by calcineurin inhibition: Hope or hype? Circ Res 1999;84:623-32.  Back to cited text no. 75
    
76.
Akazawa H, Komuro I. Roles of cardiac transcription factors in cardiac hypertrophy. Circ Res 2003;92:1079-88.  Back to cited text no. 76
    
77.
Lange AW, Yutzey KE. NFATc1 expression in the developing heart valves is responsive to the RANKL pathway and is required for endocardial expression of cathepsin K. Dev Biol 2006;292:407-17.  Back to cited text no. 77
    
78.
Liu Q, Chen Y, Auger-Messier M, Molkentin JD. Interaction between NFκB and NFAT coordinates cardiac hypertrophy and pathological remodeling. Circ Res 2012;110:1077-86.  Back to cited text no. 78
    
79.
Serfling E, Berberich-Siebelt F, Avots A, Chuvpilo S, Klein-Hessling S, Jha MK, et al. NFAT and NF-kappaB factors-the distant relatives. Int J Biochem Cell Biol 2004;36:1166-70.  Back to cited text no. 79
    
80.
Pu WT, Ma Q, Izumo S. NFAT transcription factors are critical survival factors that inhibit cardiomyocyte apoptosis during phenylephrine stimulation in vitro. Circ Res 2003;92:725-31.  Back to cited text no. 80
    
81.
Nilsson J, Nilsson LM, Chen YW, Molkentin JD, Erlinge D, Gomez MF, et al. High glucose activates nuclear factor of activated T cells in native vascular smooth muscle. Arterioscler Thromb Vasc Biol 2006;26:794-800.  Back to cited text no. 81
    
82.
Daskoulidou N, Zeng B, Berglund LM, Jiang H, Chen GL, Kotova O, et al. High glucose enhances store-operated calcium entry by upregulating ORAI/STIM via calcineurin-NFAT signalling. J Mol Med (Berl) 2015;93:511-21.  Back to cited text no. 82
    


    Figures

  [Figure 1], [Figure 2]


This article has been cited by
1 Effects of omega-3 fatty acids and metformin combination on diabetic cardiomyopathy in rats through autophagic pathway
Salma M. Eraky,Nehal M. Ramadan
The Journal of Nutritional Biochemistry. 2021; 97: 108798
[Pubmed] | [DOI]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Putative Mechani...
Role of Cathepsi...
Calcineurin/Nucl...
Crosstalk betwee...
Summary and Pers...
References
Article Figures

 Article Access Statistics
    Viewed1684    
    Printed165    
    Emailed0    
    PDF Downloaded134    
    Comments [Add]    
    Cited by others 1    

Recommend this journal