**3. Stress associated cardiovascular diseases**

High-energy stress imposes mitochondria to be more prone to injury. High-energy demanding tissues, such as the myocardium, are also more sensitive to mitochondrial dysregulation. The prevalence of cardiovascular diseases (CVD) is significantly increased in aging persons. CVD are a main cause of morbidity and mortality in the world and their incidence is closely correlated with age [22]. The cardiovascular system is a closed network containing arteries, veins and capillaries. Apoptosis is one of the most common patterns of programmed cell death in the cardiovascular system [23]. Bcl-2 is an anti-apoptotic protein mainly located in the nuclear and mitochondrial membrane, but the family member Bax, that promotes apoptosis, is mainly located in the cytoplasm [24]. The mechanism of mitochondrial transfer-induced anti-apoptosis might involve the decrease of Bax/Bcl-2 ratio and the inhibition of caspase-3 activity [25]. Thus, mitochondria have a critical role in oxidative stress related CVD (**Figure 1**).

Furthermore, chronic inflammation promotes intimal thickening and plaque formation which narrows the vascular lumen and compromises blood flow. Oxidative stress contributes to atherosclerotic plaque formation via induction of endothelial dysfunction, vascular inflammation, and accumulation of oxidized low-density lipoproteins [26].

CVD are characterized by increased levels of ROS formation due to an imbalance between pro-oxidative enzymes (xanthine oxidase, NADPH oxidase) and antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx), resulting in a deviation of cellular redox environment from the

**Figure 1.** *Oxidative stress and cardiovascular diseases: The role of mitochondria.*

normal [27]. NADPH oxidase (NOX) plays a crucial role in determining the redox state of the heart [28, 29]. Importantly, NOX enzymes have been implicated in the pathophysiology of many CVD, including atherosclerosis, hypertension and heart failure [30]. In the cardiomyocyte, ROS may be generated in the mitochondria at the ETC, by monoamine oxidase, by nicotinamide adenine dinucleotide phosphate, NOX and uncoupling of nitric oxide oxidase. Metabolic disorders increase mitochondrial protein acetylation, which directly contributes to mitochondrial dysfunction in cardiovascular diseases and heart failure [31]. Cardiac dysfunction associated with metabolic disorders such as diabetes, high blood pressure, and obesity causes the activation of mitochondria apoptotic signaling pathways and cardiomyocyte contractile dysfunction [32].
