Mitochondria and Their Role in Cardiovascular Disease

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Proper mitochondrial function is necessary in tissues and organs that are of high energy demand, including the heart. Mitochondria are very sensitive to nutrient and oxygen supply and undergo metabolic adaptation to the changing environment.


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In CVD, such an adaptation is impaired, which, in turn, leads to a progressive decline of the mitochondrial function associated with abnormalities in the respiratory chain and ATP synthesis, increased oxidative stress, and loss of the structural integrity of mitochondria. Uncoupling of the electron transport chain in dysfunctional mitochondria results in enhanced production of reactive oxygen species, depletion of cell ATP pool, extensive cell damage, and apoptosis of cardiomyocytes. Mitophagy is a process, during which cells clear themselves from dysfunctional and damaged mitochondria using autophagic mechanism.

Deregulation of this process in the failing heart, accumulation of dysfunctional mitochondria makes the situation even more adverse. Das et al. For example, Pillai et al. In general, cardiac cells control the rate of mitochondrial biogenesis through SIRT1-dependent pathways which protect against oxidative stress and inhibit the intrinsic pathway of apoptosis Mitochondrial dysfunction affects endothelial cells since aged mitochondria produce large amounts of ROS and have decreased expression of antioxidant enzymes such as SOD-2 and thioredoxin reductase.

Excessive ROS enhance the formation of peroxynitrite which impairs endothelial nitric oxide NO synthase and NO mediated dilatation 66 , Therefore, mitochondrial ROS are linked to endothelial dysfunction and their targeting improves endothelial function Moreover, stimulation of renin angiotensin system RAS induces hyperpolarization of inner mitochondrial membrane and cell death especially in cells with defective autophagy systems Additionally, mitochondrial ROS inhibit smooth muscle cell relaxation of the perivascular adipose tissue and induce the formation of endothelial extracellular vesicles which contain the proteins parkin and MFR1 In conclusion, proper mitochondrial function belongs to the most important compensatory mechanisms against vascular aging.

Therefore, interventions which target calcium entry in mitochondria would prevent smooth muscle contraction and ameliorate arterial dilatation However, the impact of mitochondrial ROS on endothelial function has to be studied intensively since overexpression of catalase, which is an important anti-oxidant enzyme, induces endothelial dysfunction in mice models Atherosclerosis is a chronic inflammatory process and the most common substrate of coronary artery disease CAD. CAD is the leading cause of death in the developed world and is characterized by acute or chronic ischemia due to insufficient myocardial oxygen supply Mitochondria have an important role in the pathophysiology of atherosclerosis Figure 4.

Mitochondrial DNA is especially prone to oxidative damage since it lacks histones and has a minor capacity for repair; furthermore, mitochondrial DNA mutations trigger the induction of a vicious cycle of ROS production as mentioned in a previous section For example, studies in apo-E deficient mice which lacked the anti-oxidant enzyme SOD-2 have demonstrated that excessive production of ROS damaged mitochondrial DNA and accelerated the progression of atherosclerosis and proliferation of vascular smooth muscle cells VSMCs Moreover, a study in humans who underwent intravascular ultrasound characterization of coronary artery plaques indicated that mitochondrial DNA damage of leukocytes is associated with the existence of vulnerable plaques but not with plaque burden Oxidized LDL molecules ox-LDL are absorbed by macrophages which display scavenger receptors on their surface and form foam cells which are rich in lipids and cell debris Foam cells release a number of pro-inflammatory mediators such as adhesion molecules and circulating cytokines which attract inflammatory cells to the damaged vascular wall.

These mediators stimulate the formation of neo-intima through hyperplasia, migration and proliferation of VSMCs Moreover, atherosclerosis is characterized by increased apoptosis of VSMCs and vascular wall remodeling. Studies in cultures of human aortic endothelial cells indicate that ox-LDL or glycated ox-LDL decrease the expression of cellular anti-apoptotic proteins and stimulate mitochondrial apoptotic pathways 80 , To sum up, mitochondrial dysfunction is responsible not only for the initiation but also the progression of the atherosclerotic vascular disease and is, therefore, an important target for the treatment of CAD.

The role of mitochondrial dysfunction in cardiovascular disease: a brief review.

Ischemic heart disease is the leading cause of mortality and morbidity in the modern world and its most common clinical presentation is acute ischemia. Early and successful reperfusion is the key against acute myocardial ischemia and can be achieved either pharmaceutically or mechanically through surgical intervention or coronary artery stenting.

Prolonged ischemia results in the death of cardiac cells due to insufficient oxygen supply. However, it has been proved that cells around the area of the infarct are at risk of further, delayed damage upon reperfusion, when oxygen supply is replenished. It is really interesting that in both conditions ROS formation are the determinants of the final damage which is comprised by increased fibrosis, angiogenesis, and vascular remodeling During ischemia cardiomyocytes become hypoxic and deteriorate the function of mitochondrial respiratory chain enzymes; therefore, superoxide, hydrogen peroxide, peroxynitrite and hydroxyl radical are formed.

Decreased functional capacity of complex I function is linked to damaged mitochondrial cardiolipin which accelerates electron leakage and stimulates a vicious cycle of free radical generation It has been demonstrated that during post-ischemic reperfusion the enhanced activity of MAO-A is responsible for the precipitation of hydrogen peroxide and the progression towards left ventricle hypertrophy and cardiac remodeling.

Also, increased influx of mitochondrial iron stimulates the formation of more potent and deleterious hydroxyl radical groups from hydrogen peroxide Additionally, Li et al. Specifically, protein kinase C PKC phosphorylates critical substrates which are involved in the clearance of damaged mitochondria and inhibit the apoptosis of dysfunctional organelles Moreover, reperfusion induces the opening of mPTP channel which stimulates the release of cytochrome c and apoptosis.

Interestingly, in a recent study in patients with acute coronary syndromes it was found that free circulating mitochondrial DNA in blood could predict cardiovascular mortality at 30 days It is important to mention that ROS production by two different phenomena might be beneficial for cardiovascular system. The first one is ischemic preconditioning and is defined as the production of sublethal amounts of ROS during short cycles of ischemia and reperfusion which results in cardio-protection. It was first identified in by Murry et al.

In general, the pathophysiological mechanism involves activation of PKC epsilon which stimulates mitochondrial KATP channels; then increased production of H 2 O 2 exerts protective actions through blockage of mPTP channel The second one is remote ischemic conditioning and was firstly described in by Przyklenk et al.

The underlying mechanism is the synthesis of factors in a remote organ which induce protective actions in remote organs through complex neuro-humoral interactions as previously described for ischemic preconditioning Hypertension is one of the most important risk factors for the development of CAD Mitochondrial dysfunction in hypertension results in impaired energy production and deficient calcium homeostasis 82 , 94 ; moreover, the decreased activity of anti-oxidant enzymes and oxidative modification of cellular compartments is associated with damage in the heart, the brain, the kidneys and the vessels 79 , 95 Figure 4.

Interestingly, it has been found that the increased prevalence of hypertension in aged people is linked to impaired mitochondrial metabolism and reduction in the activity of SIRT3 protein. Well-functioning mitochondrial anti-oxidant systems such as SOD-2 prevent the damage induced by excessive ROS formation in hypertension due to ageing or high-salt diet However, mutations in mitochondrial tRNA result in the development of hypertension, hypercholesterolemia and hypomagnesemia especially in subjects of 30 years of age indicating the detrimental effects of environmental factors and ageing on mitochondrial anti-oxidant capacity Activation of RAS system has an important role in the pathophysiology of hypertension.

Additionally, blood pressure levels regulate the production of ROS through the functions of mechano-sensitive receptors Furthermore, hypertension is associated with structural mitochondrial abnormalities which involve decreased mitochondrial mass, density and mitochondrial dwelling that result in impaired energy production and accelerated formation of ROS through instability of ETC complexes , Moreover, hypertension is linked to decreased functional capacity of complex-I system, and stimulation of of fibrosis and extracellular cell matrix expansion which further deteriorate myocardial contractility Similarly, the raised expression of biomarkers of mitophagy promotes altered expression of calcium cycling proteins which result in interstitial fibrosis of left ventricle and diastolic dysfunction Hypertension also affects mitochondrial biogenesis and dynamics which affect energy production For instance, studies in hypertensive rats have indicated decreased mRNA expression of the fusion proteins mitofusin-1 and -2, and optic atrophy-1 which implicated in mitochondrial fragmentation and stimulation of oxidative stress Moreover, oxidative stress provokes the expression of several pro-inflammatory molecules in several models of hypertension.

Finally, it has been demonstrated that hypertension is associated with the activation of apoptosis. Reduced expression of cardiolipin, which is an important phospholipid for the balanced function of mitochondria, induces the release of cytochrome c to cytosol and triggers the pathway of apoptosis , Similarly, in a study in hypertensive rats it was revealed that activation of RAS system decreased the functions of complex-III system, ATP synthase, creatine kinase and it enhanced the release of cytochrome c and caspase-3 from the dysfunctional organelles In conclusion, mitochondrial dysfunction is highly present in hypertension which indicates the importance of early therapeutic management based on the molecular level.

Metabolic syndrome and diabetes mellitus DM belong to the most challenging medical problems of the 21st century. DM is a chronic disease which affects numerous people independently of age, race and sex and is characterized by hyperglycemia and altered lipid, protein and carbohydrate metabolism , DM affects almost every tissue including vascular system, heart, retina, kidneys and peripheral nerves and several mechanisms have been implicated in the pathophysiology of the disease such as decreased physical activity, obesity, elevated free fatty acids, genetic factors, oxidative stress and mitochondrial dysfunction , Figure 4.

Mitochondria are the central organelles for ATP production through oxidative phosphorylation In general, the mechanisms of mitochondrial dysfunction involve the decrease in mitochondrial content in tissues such as muscles, liver and adipose tissue, the absence or dysfunction of mitochondrial proteins and reduced mitochondrial biogenesis Beta oxidation is the main source of energy for the heart.

However, excess delivery of fatty acids in diabetes and metabolic syndrome results in decreased oxygen utilization by mitochondria and uncoupling of ETC systems. Also, decreased mitochondrial density and reduced production of mitochondrial proteins due to mitochondrial DNA mutations or deletions is evident , , Additionally, alterations in lipid extent and metabolism and the impairment of oxidative phosphorylation increase the accumulation of diacylglycerols and ceramides which block insulin secretion and favor the progression to metabolic syndrome and type 2 DM Lastly, the excessive amounts of lipids target the downstreams of insulin receptor substrate IRS and Akt pathways resulting in insulin resistance However, this damage is usually found in a rare kind of diabetes initially described as maternally inherited diabetes and deafness syndrome induced by AG mutation of mitochondrial DNA The unopposed production of ROS elicits decreased NO synthesis in diabetic hearts which leads in structural alterations of cardiac proteins that negatively affect cardiac muscle relaxation and diastolic dysfunction in diabetic mice Moreover, evidence from human studies indicates that patients with type 2 DM display dysfunctional myocardial contractility due to mitochondrial dysfunction.

ROS alter mitochondrial dynamics and specifically increase mitochondrial fission and fragmentation at the expense of mitochondrial fusion Little is known about the exact mechanisms but nuclear respiratory factors NRF 1 and 2 are considered to play an important role NRF1 and 2 regulate the expression of Tfam, a transcription factor of mitochondrial genome, and numerous other mitochondrial genes implicated in oxidative phosphorylation.

Although NRFs and Tfam are necessary for mitochondrial biogenesis, Tfam knockout experimental studies have not yet linked Tfam and NRF disorders with the development of insulin resistance and metabolic syndrome despite the significant changes in mitochondria morphology and density According to new studies, mitochondrial dysfunction and insulin resistance are linked to altered gene expression of PCG1 in muscle and liver tissues , Specifically, it has been demonstrated that downregulation of PGC1a leads to impaired mitochondrial biogenesis and the induction of insulin resistance In conclusion, mitochondrial dysfunction is closely related to the pathophysiology of DM; therefore, targeting mitochondrial function belongs to the most prominent therapeutic interventions against the spectrum of metabolic disorders.

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HF is the result of numerous cardiac diseases and has a rapidly increasing prevalence due to the effectiveness is primary and secondary prevention of cardiovascular diseases , The initial response to increased cardiac workload is cardiac hypertrophy which is defined as the thickening of ventricular wall and reduction in ventricular volume Interestingly, mitochondrial dysfunction is an object of intense investigation in order to understand this complex clinical syndrome and discover novel molecular therapeutic targets Figure 4. However, pathologically hypertrophied hearts display a metabolic shift to increased utilization of glucose than fatty acid oxidation, which is a metabolic pattern of the fetal age - Specifically, Heather et al.

Moreover, de las Fuentes et al. Excessive ROS production and impaired function of the anti-oxidant systems are associated with the development of cardiac hypertrophy, remodeling and HF , Similarly, in a model of experimental myocardial infarction in rats it was observed a significant increase in the formation of hydroxyl radicals and reduced copies of mitochondrial DNA and transcripts of I, III and IV complexes Lower activity or defects in mitochondrial complexes I, III, IV, V in dogs, rats and human frozen-thawed cardiac-muscle samples have been demonstrated too , Another important feature of HF is the development of fibrosis and cardiac remodeling.

For example, in a model of pacing-induced supraventricular tachycardia in pigs it was demonstrated that MMP 1, 2 and 3 induce left ventricle dysfunction and dilation of left ventricle at 7 days Mitochondrial dysfunction in HF also induces impaired mitochondrial biogenesis. Studies in both human and rat models of HF have indicated small and fragmented mitochondria and lower levels of OPA1 implying the participation of mitochondrial fission in cardiac remodeling Similarly, calcium overload stimulates mitochondrial fission and formation of fragmented mitochondria Moreover, defective mitophagy in HF impairs myocardial function since damaged and non-functional mitochondria are important sources of ROS For example, in an experimental model of parkin knockout Drosophila, it was indicated that blockage of mitophagy increased the number of dysfunctional mitochondria in heart tubes which resulted in the development of dilated cardiomyopathy Lastly, it is important to note that systolic and diastolic dysfunction of the failing myocardium is provoked by the detrimental effects of ROS on sarcomeric and excitation-contraction coupling proteins.

Other vulnerable sarcomeric proteins are myosin light chain-2, myosin light polypeptide-3, alpha-actin, troponin T, actin, desmin and tropomyosin , In conclusion, normal cardiac hypertrophy is a totally different phenotype from pathologic cardiac hypertrophy based on the molecular level. Subsequently, further research on mitochondrial function in HF is crucial due to the central role of mitochondria in energy production. It is undeniable that the breakthroughs in primary and secondary prevention of cardiovascular disease have improved the lives of million people worldwide.

Several therapeutic strategies have been examined such as dietary changes, exercise and medications which target the mechanisms of oxidative stress, inflammation, cardiac hypertrophy, fibrosis and apoptosis with, however, controversial results - Figure 5. To begin with, certain dietary interventions have been tested in both animal and human models. For example, the administration of 2 gr L-carnitine daily had a survival benefit in patients with HF Similarly, in patients with mild diastolic HF the consumption of 9 g L-carnitine per day for a period of 3 months resulted in improvement of diastolic dysfunction Also, in a model of experimental hypertension the administration of L-carnitine improved cardiac remodeling through decreased ROS production Polyphenols such as flavolons, theaflavin and epicatechin are chemical compounds present in a variety of natural sources such as red wine, green tea, olive oil and dark chocolate Polyphenols have important anti-oxidant actions against several chronic diseases including cardiovascular disease , For example, quercetin decreases the levels of superoxide and increases urinary excretion of nitrate, endothelial NO synthase activity and heme oxygenase-1 protein which has anti-oxidant actions Moreover, polyphenols of olive oil and red wine reduce intracellular ROS levels whereas epicatechin of green tea lowers the expression of pro-inflammatory molecules Vitamins C and E are popular anti-oxidant molecules and have beneficial actions against a large group of chronic diseases Large clinical trials have exhibited disappointing results against mitochondrial dysfunction.

Possibly, mitochondria absorb only a small percent of these anti-oxidants or there are unknown interactions with other therapeutic, regimens unspecified pro-oxidant actions or genetic variability response among the subjects which explain these inconsistent findings - On the other hand, several studies have examined the role of co-enzyme Q10 CoQ10 in animal and human trials.

CoQ10 is present in the inner mitochondrial membrane and is important for the production of ATP; also, it possesses anti-thrombotic and anti-oxidant actions and improves hypertension and hyperglycemia Administration of CoQ10 in hypertensive rats improved endothelial function and decreased cardiac hypertrophy Though, CoQ10 does not increase mitochondrial DNA replication and does not hinder the degradation of mitochondrial cardiolipin - CoQ10 has been administrated in humans to alleviate muscle pain upon treatment of statins Interestingly, it was found that supplementation of mg daily CoQ10 for 30 days improved muscle pain in patients receiving statins In short, CoQ10 is considered a safe option for the treatment of mitochondrial dysfunction in humans and can be administrated alone or along with other medications against hypertension and HF although its properties are not fully elucidated in ischemic heart disease Moreover, a current strategy is to administrate anti-oxidant molecules which are conjugated to lipophilic molecules in order to selectively target mitochondria , For example, the recently developed MitoQ10 improves endothelial NO bioavailability and blood pressure in a model of spontaneously hypertensive rats Addition of MitoQ10 to treatment with losartan has revealed beneficial actions against target organ damage development in hypertension Regular physical activity has beneficial actions on cardiovascular system Aerobic exercise increases the production of NO, lowers the levels of superoxide and hydrogen peroxide and improves endogenous enzymatic anti-oxidant systems , Also, it reduces systolic and diastolic blood pressure in hypertensive subjects, whereas isometric exercise affects only systolic blood pressure , Nevertheless, the exact mechanisms of exercise on mitochondrial function are not yet elucidated.

Similarly, in animal models of diabetes resveratrol hindered the progression to diabetic cardiomyopathy Excessive fatty acid oxidation is linked to the development of several metabolic disorders such as obesity and DM.

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Therefore, it seems reasonable that decreased uptake and utilization of fatty acids could be beneficial. For example, exercise, calorie restriction and weight loss such as that achieved through bariatric surgery improve insulin sensitivity and mitochondrial function , Moreover, inhibition of CD36 which mediates lipid uptake through plasma membrane decreases mitochondrial oxidative stress in animal models; however, targeting of CD36 has not been tested in humans due to the pleiotropic functions of this receptor in humans Apart from the above agents, widely prescribed medications have demonstrated beneficial actions against mitochondrial dysfunction.

Targets of RAS system activation such as ACE inhibitors and angiotensin receptor-II blockers improve mitochondrial dysfunction; for instance, captopril increased mitochondrial biogenesis in an experimental study in dogs - Also, treatment with losartan and amlodipine reduced blood pressure in spontaneously hypertensive rats whereas only losartan restored mitochondrial dysfunction and kidney damage through preservation of glutathione and SOD activity Statins apart from inhibition of endogenous cholesterol synthesis display important pleiotropic effects - Specifically, they decrease oxidative stress in various tissues targeting mitochondrial function Parihar et al.

Metformin, the first line therapy for patients with type 2 DM, has exhibited several beneficial actions on cardiovascular system Recent research has shed light to the role of micro-RNAs miR which are involved in transcription of cellular genes that either promote or prevent the development of disease - Interestingly, a study in rats indicated that overexpression of miR is linked to improved cardiac function and decreased infarct size post myocardial infarction; also, low levels of miR were confirmed in vitro in hypoxia-treated cardiomyocytes.

Moreover, miR targets PDCD4 gene which is involved in the apoptotic pathway and it seems that mimics of this agent could be used in the treatment of myocardial infarction Edaravone is a novel free radical scavenger. Edaravone reduced pressure overload-induced left ventricular hypertrophy in mice through inhibition of Ask1 and its downstream kinases Also, it diminished perivascular and intermuscular fibrosis and improved cardiac hypertrophy even when treatment was initiated after the onset of cardiac hypertrophy Elamipretide SS is a novel, water-soluble tetrapeptide which enhances mitochondrial energy production.

Elamipretide binds selectively to cardiolipin and preserves the structure of mitochondrial cristae and the function of oxidative phosphorylation Interestingly, in a study in dogs with advanced HF Elamipretide improved left ventricular function and enlargement, plasma natriuretic peptides and biomarkers of inflammation through decreased ROS formation Moreover, in a randomized, placebo-controlled trial in humans with HF and reduced ejection fraction it ameliorated left ventricular end-diastolic and end-systolic volume Lastly, in a study in rats it improved mitochondrial oxidative stress mediated by angiotensin-II through inhibition of p38 MAPK pathway and hindered cardiac remodeling and inflammation post myocardial infarction In conclusion, several medications have been tested for the therapy of mitochondrial dysfunction with controversial results so far.

Novel therapeutic strategies involve the design of molecules which target specific pathways of mitochondrial function. Mitochondria are cellular organelles which produce energy through oxidative phosphorylation and their function is crucial for the heart due to the high energy demands.

Mitochondrial dynamics consist of a balance between mitochondrial fusion and mitochondrial fission which controls energy production. On the other hand, mitophagy is an important mechanism of removal of the dysfunctional organelles. Several cardiac diseases such as atherosclerosis, ischemia-reperfusion injury, hypertension, diabetes and heart failure are linked to improper mitochondrial function and excessive production of ROS which damage cellular lipids, proteins, enzymes and DNA.

Mitochondrial dysfunction is also associated with apoptosis which accelerates cardiovascular damage. Numerous therapeutic interventions against mitochondrial dysfunction have been tested in both animal and human models and research in this field is constantly advancing. Conflicts of Interest: The authors have no conflicts of interest to declare. National Center for Biotechnology Information , U.

Journal List Ann Transl Med v. Ann Transl Med. Papavassiliou 5. Panagiota K. Athanasios G. Author information Article notes Copyright and License information Disclaimer. Corresponding author.

The role of mitochondrial dysfunction in cardiovascular disease: a brief review.

Email: rg. Received Mar 30; Accepted May 2. Copyright Annals of Translational Medicine. All rights reserved. This article has been cited by other articles in PMC. Abstract Mitochondria are the source of cellular energy production and are present in different types of cells. Keywords: Mitochondria, cardiovascular disease, oxidative stress, treatment.

Introduction

Introduction Mitochondria are cellular organelles of maternal origin which are involved in energy production through the process of oxidative phosphorylation. Cardiac mitochondria: description of origin, function, network and biogenesis Mitochondria are highly present in cardiac cells due to the increased energy demands and are responsible for the daily production of approximately 6 kg of ATP through the process of oxidative phosphorylation 8 Figure 1.

Open in a separate window. Figure 1. Figure 2.

Cardiac mitochondria and regulation of oxidative stress Mitochondria are the powerhouse of the cell. Figure 3. The balance between oxidative stress and anti-oxidant actions.

The Relationship Between Stress and Cardiovascular Disease

Cardiac mitochondria and endothelial function Mitochondrial dysfunction affects endothelial cells since aged mitochondria produce large amounts of ROS and have decreased expression of antioxidant enzymes such as SOD-2 and thioredoxin reductase. Mitochondrial function in coronary atherosclerosis Atherosclerosis is a chronic inflammatory process and the most common substrate of coronary artery disease CAD. Figure 4. Mitochondrial function in hypertension Hypertension is one of the most important risk factors for the development of CAD Mitochondrial function in cardiac hypertrophy and HF HF is the result of numerous cardiac diseases and has a rapidly increasing prevalence due to the effectiveness is primary and secondary prevention of cardiovascular diseases , Mitochondrial dysfunction: therapeutic implications It is undeniable that the breakthroughs in primary and secondary prevention of cardiovascular disease have improved the lives of million people worldwide.