Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 5  |  Issue : 3  |  Page : 109-117

Cardioprotective effect of alpha-lipoic acid and its mechanisms


1 Institute of Biomedical Sciences, Fudan University, Shanghai, China
2 Institute of Biomedical Sciences; Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, China

Date of Submission30-Apr-2020
Date of Acceptance23-Jul-2020
Date of Web Publication21-Sep-2020

Correspondence Address:
Ai-Jun Sun
Institute of Biomedical Sciences, Fudan University, Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cp.cp_16_20

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  Abstract 


Alpha-lipoic acid (ALA), a sulfur-containing fatty acid ubiquitously present in living organisms, is a cofactor that covalently binds to mitochondrial enzymes, such as pyruvate dehydrogenase (PDH) and oxoglutarate dehydrogenase (OGDH). ALA is not only crucial to the function of major enzymes that provide carbon to the tricarboxylic acid cycle but also has strong antioxidant properties. Indeed, ALA has a variety of properties under physiological and pathological conditions. In particular, ALA has been shown to have a protective effect on the cardiovascular system. The specific mechanisms may involve an anti-oxidative stress role by scavenging reactive oxygen species (an antioxidant property), regulation of aldehyde dehydrogenase-2 (ALDH2), and anti-inflammatory properties. The present review discusses the endogenous disulfide compound ALA, with a focus on its roles in cardioprotection and the underlying mechanisms.

Keywords: Aldehyde dehydrogenase; Antioxidant; Cardiovascular disease; Thioctic acid; α-lipoic acid


How to cite this article:
Hu QF, Sun AJ. Cardioprotective effect of alpha-lipoic acid and its mechanisms. Cardiol Plus 2020;5:109-17

How to cite this URL:
Hu QF, Sun AJ. Cardioprotective effect of alpha-lipoic acid and its mechanisms. Cardiol Plus [serial online] 2020 [cited 2020 Oct 21];5:109-17. Available from: https://www.cardiologyplus.org/text.asp?2020/5/3/109/295637




  Introduction Top


Alpha-lipoic acid (1,2-dithiolane-3-pentanoic acid, ALA), also known as lipoic acid (LA) or thioctic acid, was first identified in the 1950s by Reed et al.[1] and Patterson et al.[2] A better understanding of the chemical properties and biological functions of ALA has developed over the past two decades. ALA is an endogenous disulfide compound, which in humans is synthesized de novo in liver mitochondria and other tissues. It is a key cofactor for α-keto acid decarboxylation and covalently binds to multiple enzyme complexes, such as pyruvate dehydrogenase.[3]

Basic research and clinical trials have revealed that ALA has multiple roles and is effective in the treatment of some diseases. Indeed, various studies have reported that ALA can positively affect the outcome of cardiovascular disease (CVD) through various molecular pathways.[4],[5] Accordingly, the purpose of this review is to deepen the understanding of the application of ALA in the treatment of diseases of the cardiovascular system.


  Characteristics and Application of Alpha-Lipoic Acid Top


ALA is an organosulfur compound synthesized from octanoic acid in mitochondria of plant and animal cells. In cells, ALA is usually present in its more bioactive reduced form, dihydrolipoic acid (DHLA), which is responsible for most of its antioxidant effects. ALA contains two thiol groups, either oxidized or reduced, that form part of a redox pair. Both the oxidized and reduced forms of ALA are antioxidants.[6] Dietary ALA is quickly absorbed and accumulates in several tissues, but a major proportion is converted to DHLA by lipoamide dehydrogenase in specific tissues.[7] Both ALA and DHLA have a chiral center which can provide special optical properties. Specifically, ALA has two enantiomers: R-enantiomer (R-ALA or [+]ALA) and S-enantiomer (S-ALA or [−]ALA). However, ALA only exists as the R-enantiomer in nature.

ALA acts as a cofactor for various enzymes, including the PDH complex and oxoglutarate dehydrogenase complex (OGDHC), in mitochondria. These two mitochondrial enzyme complexes, which are involved in glucose metabolism, are part of the citric acid cycle (Krebs cycle or tricarboxylic acid cycle), and thus assume the core role of general energy production. In other words, ALA is essential in the metabolism of carbohydrates, lipids, and proteins, ultimately generating energy in the form of adenosine triphosphate (ATP).[8],[9],[10] The chemical activity of ALA and DHLA is based on the dithiolane ring. Besides, the position of the two sulfur atoms in the ring produces an unusually high electron density, which gives ALA its special properties. Cysteine residues of cytoplasmic and mitochondrial proteins usually contain sulfhydryl groups, and the oxidation of these sulfhydryl groups to disulfide bonds or other cysteine forms changes the function and activity of the proteins.[11] DHLA exerts an antioxidant effect by donating electrons directly to co-oxidants or oxidized molecules. It should be noted that DHLA is the only known low-molecular-weight physiological dithiol in humans and other animals. It can regenerate and restore Vitamin C from dehydroascorbic acid and indirectly regenerate Vitamin E from its oxidized state.[6] ALA was first shown to act as an antioxidant by its ability to improve Vitamin C and E deficiency in guinea pigs and rats.[12] An extensive literature [13],[14] has already shown that ALA can exert a significant antioxidant effect through its free radical scavenging activities,[15] such as by directly removing reactive oxygen species (ROS) and reactive nitrogen oxide species (RNOS), its metal chelating ability,[16] mediating the recycling of other endogenous antioxidants (such as glutathione and Vitamins C and E),[6] and repairing oxidative damage. The presence of thiol groups in ALA determines its metal chelating ability.[17] In addition, ALA metabolites have been shown to have anti-inflammatory effects.[18] Thus, the chemical properties of ALA and DHLA enable them to participate in important biochemical reactions.

ALA is well established as a therapy for preventing diabetic neuropathy (DN). It improved nerve blood flow, reduced oxidative stress, and improved distal nerve conduction in an experimental DN rat model.[19] A clinical study examining the effect of ALA on neuropathic symptoms in patients with DN demonstrated that ALA administration was associated with reduced neuropathic symptoms and triglycerides and improved quality of life.[20] Although some clinical trials have been conducted on the anti-obesity effects of ALA,[21],[22],[23] several studies have shown that ALA has no significant effect on weight reduction.[24] However, a systematic review and meta-analysis of clinical trials of ALA supplements for the treatment of obesity have revealed that supplementation with ALA significantly, albeit slightly, reduces body weight and body mass index.[25] Another study on the effects of ALA in patients with schizophrenia showed that ALA can improve plasma adiponectin levels and may have a potential role in the treatment of metabolic risk factors in such patients.[26] A 2-year, randomized, double-blind pilot study examining the effects of 1200 mg daily oral dose of ALA, on gait and balance, demonstrated that ALA affected walking performance in people with secondary progressive multiple sclerosis, particularly in those with lower baseline disability.[27] ALA is very helpful in preventing miscarriage and preterm delivery and the safety of oral ALA treatment in pregnant women was reported in a retrospective observational study.[28] Furthermore, the protective effect of ALA on liver and kidney–pancreas transplantation patients has also been reported.[29],[30] In recent years, there has been an increasing interest in the role of ALA in CVD.


  Effect of Alpha-Lipoic Acid on Cardiovascular Disease Top


Atherosclerosis

Atherosclerosis is a disease in which atherosclerotic plaques form on the walls of blood vessels and cause arterial stenosis or narrowing. The risk factors for atherosclerosis are mainly hyperlipidemia, smoking, diabetes, hyperhomocysteinemia, and hypertension.[31] However, the mechanisms mediating the effects of these factors on the disease process and the interactions between them remain unknown to a certain extent. The commonality of these risk factors is oxidative stress.[31] The hypothesis that oxidative stress is a major cause of atherosclerosis is increasingly being accepted.[32] It posits that in early lesions of atherosclerosis, increased oxidative stress causes inflammatory events, which, in turn, lead to the production of peroxides, superperoxides, and hydroxyl radicals in endothelial cells. The inflammatory process perpetuates the cycle of vascular system damage.[33] Therefore, current research has focused on the role of antioxidants showing protective effects against the oxidation of low-density lipoprotein cholesterol, which may lead to inhibition of the atherosclerotic process. Accordingly, we have reason to believe that antioxidant supplements would significantly contribute to reducing the risk of some diseases associated with the atherosclerotic process, such as heart disease, stroke, and hypertension.[34]

In addition, the preventive effect of antioxidant therapy on atherosclerosis has also been widely explored experimentally.[35],[36],[37] The anti-atherosclerotic effects of ALA have been demonstrated on apoE -/- mice with streptozotocin-induced diabetes, leading to aortic atherosclerosis, and on rabbits fed with 100 g/rabbit/day of a 1% cholesterol-rich diet, to induce hypercholesterolemia.[38],[39] These studies showed that ALA significantly reduces T cell infiltration in atherosclerotic lesions.[40] When the endogenous level of ALA decreases, the formation of atherosclerosis likely exacerbates.[41] Furthermore, due to the loss of estradiol, diseases caused by atherosclerosis are the main cause of death in postmenopausal women. Therefore, it is worth noting that ALA may provide a potential treatment for atherosclerosis in these women.[42] Thus, given the key role of oxidative stress and inflammation in the development of atherosclerosis, the antioxidant and anti-inflammatory properties of ALA have a major protective role in atherosclerosis. This may encourage the clinical application of ALA in patients with atherosclerosis.

Myocardial infarction

Myocardial infarction (MI) is one of the most severe cardiac events in the world, with high morbidity and mortality rates.[43] Heart failure (HF) is among the common complications of MI,[44],[45],[46] with the one-year mortality rate of patients hospitalized with HF after MI as high as 43.2%.[47]

Isoproterenol, a β-adrenergic receptor agonist, can be used to experimentally induce MI in rats. The pathological process of the isoproterenol-induced MI is driven by the oxidative stress caused by the imbalance between the oxidative system and the heart antioxidant defense system in experimental animals, which is similar to that observed in human MI.[48],[49] The experimental results revealed for the first time that ALA exerts cardioprotective effects against isopropanol-induced MI in rats, and that the myocardial protective effects of ALA and amlodipine are synergistic.[50] It was also found that the overall heart-protective effect of ALA is associated with its antioxidative effects, including its effects on the direct quenching of oxidized free radicals or the maintenance of free radical scavenging enzyme activity and glutathione levels, which can protect the myocardium from oxidative damage by reducing lipid peroxidation. Moreover, Ozgun et al. showed that injection of 10 mg/kg of ALA for 14 days can effectively prevent MI in non-diabetic rats. However, this was insufficient to change histopathological or biochemical parameters of diabetic rats.[51] The above experiments show that ALA plays an important protective role in MI in experimental animals, but more detailed experiments are needed to detect the effect of ALA on patients with MI.

Myocardial ischemia–reperfusion injury

The process of restoring blood flow to ischemic myocardium after acute MI may cause tissue damage, which is referred to as myocardial reperfusion injury. This can, paradoxically, reduce the beneficial effects of myocardial reperfusion.[52] Thus, there is an urgent need to search for novel pharmacological interventions to reduce the myocardial ischemia–reperfusion injury.

The use of ALA in myocardial ischemia–reperfusion injury is discussed and examples are given in this section. There have been some reports on the cardioprotective action of ALA or DHLA in ischemia/reperfusion injury in rat models.[53],[54],[55] The underlying mechanism includes the activation of ALDH2[53] and the activity of KATP channels.[55] However, there are contrasting views on the role of ALA in myocardial ischemia–reperfusion injury. For example, researchers in one study used two different kinds of ischemia–reperfusion models to perform a more rigorous analysis and obtain more robust results, namely the classical Langendorff system and the working heart system, and the results indicated that DHLA does not affect ischemia–reperfusion injury.[56] Interestingly, data from another study showed that DHLA alleviates hemodynamic damage after ischemia. Further, this effect of ALA on ischemia–reperfusion injury was shown to be dose-dependent:[57] low-dose DHLA has antioxidant activity against oxidative stress in heart function damage, but a 10-fold increase in the DHLA concentration is harmful.

Thus, there is no definite conclusion on the role of ALA in myocardial ischemia–reperfusion injury. Therefore, more animal studies, including different myocardial ischemia–reperfusion injury models and different doses and administration methods of ALA, need to be conducted in the future to verify the role of ALA in myocardial ischemia–reperfusion injury.

Hypertension

Hypertension is a chronic disease defined as persistently high arterial blood pressure.[58] The protective effects of ALA against hypertension have also been studied in experimental conditions.

The use of ALA can reduce blood pressure in different animal models of human hypertension, such as in spontaneously hypertensive rats,[59],[60] glucose-fed hypertensive rats,[61],[62] salt-induced hypertensive Wistar-Kyoto rats,[63] high fructose-fed hypertensive rats,[64] renovascular hypertensive rats,[65] glucocorticoid-induced hypertensive rats,[66] and high salt-induced hypertensive rats.[67] Regarding the underlying mechanism of action of ALA, it has been suggested that its antioxidant properties [61],[62],[68] and its redox partner DHLA [63] may play key roles.

As mentioned above, ALA can reduce hypertension in different human hypertension animal models; thus, its potential mechanism can further be studied in different models.


  Possible Mechanism Mediating the Effect of Alpha-Lipoic Acid on Cardiovascular Diseases Top


Effect of alpha-lipoic acid on acetaldehyde dehydrogenase-2

There is a considerable amount of research reporting a critical role of ALDH2 in cardioprotection.[69],[70],[71],[72],[73] ALA has an effect on ALDH2 mediated in part through its antioxidant properties. First, it is well established that ALDH2 has redox-sensitive thiol groups, which are inactivated by oxidation [74],[75],[76] and may also have significance in alcohol-induced cell damage and cardiac toxicity.[77],[78] DHLA is an effective dithiol reducing agent with a reductase system in mitochondria.[79],[80],[81] Several studies are showing that the mitochondrial dithiol compound DHLA restores mitochondrial ALDH2 activity by reducing disulfide bonds between cysteines in the active site.[53],[55],[82],[83],[84] In addition, DHLA did not fully restore ALDH2 activity in another study, with a possible explanation being that oxidants cause irreversible inhibition of ALDH2 (such as the formation of sulfonic acid products that cannot be reduced by dithiol compounds).[10]

ALDH2, located in the mitochondrial matrix, is mainly found in the liver, heart, brain, and lung, and plays a major role in the oxidation of acetaldehyde to acetic acid. Consensus has not been reached on the regulation of ALDH2 activity by ALA in different tissues. Shindyapina et al. concluded that ALA upregulates the expression of the ALDH2 gene during formaldehyde metabolism in the brain, especially in the hippocampus, but has little effect on the mRNA level of myocardial ALDH2.[85] High doses of ALA can increase the activity of ALDH2 in rat gastric tissues in the ethanol-induced gastric mucosal injury model.[86] In another study, blood samples from acute coronary syndrome (ACS) patients were used to measure ALDH2 activity. The ALDH2 activity increased after 24 h and 1 week of ALA treatment, with no clear description of the expression of ALDH2 in organs.[82] On the other hand, there are some conflicting opinions and conclusions. For example, ALA treatment increased ALDH2 activity in isolated rat hearts and cultured H9c2 cells, and the suggested underlying mechanism is that the regulation of ALDH2 activity by ALA is mediated through the PKCε signaling pathway.[53] In another study,[10] ALDH2 activity of heart mitochondria from either in vivo ethanol (solvent control)- or glyceryl trinitrate treated rats was increased by DHLA. In addition, ALA was also found to increase the ALDH2 activity in the myocardial tissue of diabetic rats.[87]

Reduce oxidative stress by quenching reactive oxygen species

Oxygen plays a vital role in cellular respiration. Oxygen reduction occurs in all aerobic organisms through different mechanisms, producing ROS, also referred to as free radicals. ROS are the single-electron reduction products of a group of oxygen compounds in the body. They are generated by electrons that leak out of the respiratory chain and consume about 2% of the oxygen before they can be delivered to the terminal oxidase. The reduction products are superoxide anions (O2−), two-electron reduction products, hydrogen peroxide (H2O2), three-electron reduction products, hydroxyl radicals (·OH), and nitric oxide (NO). ROS are mainly generated during the transition from Stage III to Stage IV in a high-oxygen environment and a high-reduction state of the mitochondrial respiration chain that causes a large number of electrons to leak out and reduce oxygen molecules. When NO is produced at high concentrations, it is also a source of highly toxic oxidants, collectively known as RNOS, including peroxynitrite, nitro, and nitrogen dioxide, which are formed by the reaction of NO with the superoxide anion or molecular oxygen.[88],[89],[90]

The generation of ROS is affected by various environmental factors, such as ultraviolet radiation (for example, exposure to sunlight) and tobacco smoke. To counteract the effects of ROS in the body, cells have various antioxidant defense mechanisms, including superoxide dismutase, catalase, ascorbic acid, and glutathione.

ROS produced by endogenous and exogenous sources cause damage and accumulation or aggregation of proteins, lipids, and DNA when the antioxidative defense mechanism of the body is weakened. These ROS also regulate signal transduction pathways. These disturbances can cause damage to organelles, alter gene expression, change cellular responses, and ultimately contribute to aging.[6] Overproduction of ROS and RNOS is associated with the pathogenesis and development of chronic inflammatory diseases, including atherosclerosis.[91],[92] Oxidative stress plays an important role in the etiology of many CVDs including endothelial dysfunction in atherosclerosis and ischemic heart disease, hypertension, and HF. ALA and DHLA were found to be highly reactive with various ROS and RNOS. As a natural antioxidant, ALA is believed to have a salutary role in oxidative stress parameters related to CVD.[5]

Anti-inflammatory properties of alpha-lipoic acid

ALA has also been shown to have anti-inflammatory properties. It has been reported that patients with previous inflammatory diseases have a significantly increased risk of developing CVD in youth.[93] Inflammatory biomarkers are important risk factors for CVD, and these biomarkers are important to select suitable therapeutic targets for patients with CVD.[94] Compared with healthy subjects, patients with HF have lower ejection fractions and higher pro-inflammatory cytokine blood levels.[95]

A study conducted in 2010 suggested that various inflammation parameters in aged rats, including activation of nuclear factor kappa-B (NFκb) and up-regulation of vascular cell adhesion molecule 1 (Vcam1) in the aorta and C-C motif chemokine ligand 2 (CCL2), were significantly increased. After 2 weeks of supplementation with 0.2% (R)-ALA, the mRNA level (not protein level) of Vcam1 was significantly decreased. In addition, ALA reversed the age-dependent changes in plasma CCL2 levels. Thus, inflammation increased with age and was relieved by ALA supplementation.[96] Another study indicated that ALA also inhibits tumor necrosis factor (TNF)-induced NFκB activation associated with Vcam1 and prostaglandin-endoperoxide synthase 2 (PTGS2) expression by activating the phosphoinositide 3-kinases/protein kinase B (PI3Ks/Akt) pathway in human umbilical vein endothelial cells (HUVECs). This suggests that the anti-inflammatory effect of ALA is not related to its antioxidant effect.[97] The expression of heme oxygenase 1 (HMOX1), one of two isoenzymes that initiate heme catabolism, was induced by ALA through nuclear factor erythroid 2-related factor 2 (NFE2L2) in human monocytes in vitro.[98] HMOX1 is a cytoprotective molecule, which has strong anti-inflammatory myocardial protective properties.[99] In cultured vascular smooth muscle cells (VSMCs), ALA significantly reduces the expression of C-X3-C motif chemokine ligand 1 (Cx3cl1). Cx3cl1, an adhesion molecule that plays a major role in arterial inflammation and atherosclerosis, can prevent abnormal intimal hyperplasia after vascular injury.[100] In general, ALA can regulate some genes related to anti-inflammatory signaling pathways, thus playing a regulatory role in CVD.


  Conclusion Top


The current research on the effects of ALA in certain CVDs is described above, together with the explanation of possible mechanisms mediating such effects [Figure 1]. Besides the three well-studied underlying mechanisms described above, there are additional contributing factors that deserve our close attention. For example, ALA can regulate the immune system and mitochondrial membrane potential, which may have a profound effect on CVD. As has been known for decades, the heart is the target of immunological effector organs. The immune system has a critical contribution to the development, composition, and function of the heart. Immune cells infiltrate the mother heart during pregnancy and remain in the heart muscle, where they participate in lifelong basic housekeeping functions. After MI, a large number of immune cells are recruited to the heart where they remove necrotic tissue, scavenge pathogens, and promote tissue healing. Immune cells can cause irreversible damage, thereby leading to HF in some cases. ALA is used to treat autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, primary vasculitis, and multiple sclerosis.[101] Although ALA-regulated immune system factors in some cases are important in CVD, the immunomodulatory effects of ALA in CVD need to be corroborated by further investigation. ALA and DHLA were found to promote mitochondrial permeability transition pore (mPTP) opening in rat liver, while mPTP was turned off under physiological conditions.[102] Under stress conditions, the continuous opening of mPTPs leads to the impairment of mitochondrial membrane potential,[103] whose stability maintains the normal physiological function of cells.[104] It also leads to the imbalance of oxidative phosphorylation and the depletion of ATP. These alterations eventually affect the heart's pump function, aggravate the disturbance of calcium overload in plasma, and could also cause osmotic edema of the mitochondrial matrix, rupture of the outer membrane, the release of pro-apoptotic factors such as cytochrome C, and irreversible damage, such as apoptosis and necrosis. In CVD, impaired mitochondrial function results in the decrease of ATP production and the increase of ROS generation.
Figure 1: A schematic diagram of ALA regulating CVD through three mechanisms. First, ALA or DHLA reduces oxidized thiol groups to restore ALDH2 activity. Second, ALA or DHLA quench ROS to reduce oxidative stress. Third, ALA or DHLA has anti-inflammatory properties, including the decrease of Vcam1, CCL2, NF κB and Cx3cl1, and the increase of HMOX1. ALA exerts a protective effect on CVD through the main three mechanisms above. ALA: alpha-lipoic acid, DHLA: dihydrolipoic acid, ALDH2: aldehyde dehydrogenase-2, ROS: reactive oxygen species, Vcam1: vascular cell adhesion molecule 1, CCL2: C-C motif chemokine ligand 2, NFκB: nuclear factor kappa-B, Cx3cl1: C-X3-C motif chemokine ligand 1, HMOX1: heme oxygenase 1

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The three mechanisms described in this article may not be independent of each other. In other words, the pathways of these mechanisms may crosstalk with each other.

More specifically, the regulatory role of ALA on ALDH2 activity, as well as its anti-inflammatory effect, is related, to some extent, to its anti-ROS (an antioxidant property). As mentioned above, ALA or DHLA have been found to reduce the oxidized thiol group of ALDH2, thereby restoring its activity, but such findings have been controversial to date. In atherosclerosis, increased oxidative stress leads to inflammation. There is a more complex interaction between the possible mechanisms by which ALA protects against CVD. The mPTP regulates the generation of ROS and ATP production.[105] Due to the continuous production of high levels of ROS in chronic inflammatory conditions, the endogenous antioxidant capacity could attenuate. Activated immune effector cells produce excessive ROS. Furthermore, the interaction between ROS and the immune system has been fully confirmed. On the one hand, ROS may play a significant role in signal transduction in various immune cells. For example, ROS produced by macrophages kill bacteria, and ROS released by regulatory T cells inhibit the activation of other T cells.[106] On the other hand, excessive ROS produced by immune cells could exacerbate inflammation and disrupt the balance of the immune system in pathological conditions. Oxidative stress is one of the factors leading to immune system disorders and dysfunction.[107] In recent years, it has been established that the mechanistic target of rapamycin (mTOR), controlled by redox status, plays a crucial regulatory role in the immune system. This suggests that mTOR is the key point of the link between metabolic stress and autoimmunity.[108] In the future, it will be necessary to further expand the research on the effect of ALA in CVD and its related mechanisms, which will contribute to the clinical therapeutic application of ALA in CVD.

Financial support and sponsorship

This work was supported by grants from the National Nature Science Foundation of China 81725002.

Conflicts of interest

There are no conflicts of interest.



 
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