2. Oxidative Stress and Cardiovascular Disease

The relationship between oxidative stress and cardiovascular diseases is shown in Figure 2.

Figure 2.

2.1. Oxidative Stress and Myocardial Ischemia-Reperfusion (I/R) Injury

Myocardial I/R injury is characterized by restoration of blood flow to the oxygen-deprived organs. The rapid re-establishment of blood flow leads to the oxygen burst and the ROS overproduction ^[9]. It is one of the most important pathogenic mechanism in acute coronary syndrome, myocardial infarction, surgical coronary bypass surgery, coronary revascularization intervention, circulatory shock, or organ transplantation ^[10]. Myocardial I/R injury accounts for approximately 25% of cell deaths during myocardium infarction ^[11]. The reperfusion injury can cause the “no-reflow” phenomenon, myocardial stunning, reperfusion arrhythmias, and reperfusion injury ^[12].

During reperfusion, the sources of ROS overproduction are mitochondria ^[13], NOX family ^[14], Xo ^[15], and uncoupled NOS ^[16]. Complex I and III are the major sites for ROS overproduction in myocardial I/R injury. In addition, mPTP participates in the regulation of ROS overproduction in mitochondria. Braunersreuther et al. showed that the infarcted myocardium was reduced in the NOX1 and the NOX2 deficient mice compared with the wild-type mice, while NOX4 deficient mice had no obvious phenotype ^[17]. At the same time, redox signaling, including the hypoxia-inducible factor (HIF) pathway ^[18] and Nuclear factor E2-associated factor 2 (Nrf2) ^[19] pathway, is also activated to antagonize the ROS burst. HIF is an oxygen sensitive transcription factor which is also regulated by NOX-related ROS production. HIF-1α attenuates I/R injury through the regulation of inducible NOS, heme oyxgenase-1, cyclooxygenase-2, and antioxidant enzymes. Studies by Li et al. showed that HIF also directly targets mitochondria and have a protective role ^[20]. Nrf2 is a family of transcription factors. It is located in the cytosol under normal conditions. During the oxidative stress, it is translocated into the nucleus to regulate the expression of antioxidant and anti-inflammatory factors ^[21].

Increased ROS is associated with cardiomyocyte mitochondria damage, DNA damage, and protein degradation, which all lead to irreversible cell death ^[22]. Mitochondria damages are considered as the central process of oxidative stress-mediated myocardial I/R injury. Lochner et al. showed that mitochondrial depolarization resulted in mitophagy. However, the repressed mitophagy triggered the impairment of ATP production and Ca

²⁺ overload ^[23]. Myocardial I/R injury is also associated with abnormal opening of mPTP, which could lead to apoptosis or necrosis. Cyclophilin D (CyPD) resides in the mitochondrial matrix working as a scaffold to control mPTP. Evidences show that S-nitrosylation modifications of CyPD is regulated by oxidative stress; CyPD knock-in mice show less I/R injury ^[24].

Endoplasmic reticulum stress is also regulated by oxidative stress and plays an important role in myocardial I/R injury ^[25]. Oxidative stress modifies amino acid residues to regulate protein activities and disturb intracellular Ca

²⁺-homeostasis. In addition, inflammation is of great importance in myocardial I/R injury process. After myocardial I/R injury, cytokine cascades, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), are activated. The activated cytokines will induce inflammation in these cells. Among them, neutrophils are the predominant early responder ^[26]. Neutrophils recruited to the infarct zone contain high levels of NOX2 and MPO, which facility the production of ROS. Furthermore, cytokine cascade has been shown to suppress cardiac contractility and decrease collagen synthesis ^[27].

A clinical study in patients undergoing the primary percutaneous coronary intervention showed plasma 8-iso-prostaglandin F2alpha, which is used as an indicator of oxidative stress, was increased after the procedure. However, there was no relationship between 8-iso-prostaglandin F2alpha and troponin T ^[28]. In patients undergoing coronary artery bypass surgery, thiobarbituric acid reactive substances (TBARS) was measured to indicate the oxidative stress status. The results showed that the oxidative stress was increased after surgery and the peak increase was seen 1 h after the reperfusion ^[29].

2.2. Oxidative Stress and Heart Failure (HF)

HF is characterized by the inadequate cardiac output to meet the bodily demands. Clinically, it is manifested by shortness of breath and/or chest tightness ^[30]. Studies showed that ROS are overproduced in all stages of HF ^[31]. Interestingly, the main source of ROS is different in HF patients with or without reduced ejection fraction. HF with reduced ejection fraction (HFrEF) is characterized by a reduced ejection fraction and is commonly due to coronary artery disease (CAD). In HFrEF, the injured cardiomyocytes produce ROS which leads to the maladaptive remodeling through programmed cell death and fibrosis ^[32]. In contrast, HF with preserved ejection fraction (HFpEF) is usually caused by hypertension, diabetes or genetics (e.g., hypertrophic cardiomyopathy). In HFpEF, the endothelial cells are the major sites of ROS overproduction ^[32][33]. The risk factors associated with HFpEF result in elevated plasma proinflammatory factors, such as IL-6, soluble ST2, and TNF-α. These factors act on the endothelial cells to induce ROS production, which upregulate the protein kinase G signaling in cardiomyocytes.

Mitochondria are major sites of ROS production in failing hearts while NOX and Xo activities are also increased ^[34][35]. The overproduction of ROS in HF patients causes mitochondria damage, which gives feedback to produce more ROS ^[36]. At the same time, ROS accelerates myocardial remodeling by activating variety of hypertrophic signaling kinases and transcription factors, such as tyrosine kinase Src, GTP-binding protein Ras, and mitogen-activated protein kinases (MAPKs) ^[37][38]. In addition, matrix metalloproteinases, important factors for myocardial structure, are also activated by ROS ^[39].

It is worth noting that the chemotherapy associated cardiomyopathy is a special kind of HF. It is relatively common and serious complication of chemotherapy ^[40]. Many classes of chemotherapeutic agents that are widely used in the clinics are identified to have cardiac toxicity, such as anthracyclines and alkylating agents ^[41]. These agents cause the increase in ROS generation and enhance the oxidative stress in the cell, which then leads to cardiomyocyte death ^[42]. Doxorubicin (DOX), a widely used anthracycline chemotherapeutic drug, directly modifies the mitochondrial DNA and disturbs the mitochondrial function, the protein expression, and the lipid peroxidation ^[42]. DOX combines with free iron to form iron-Dox complex, then reacts with oxygen and facilitates ROS production ^[43].

Clinical study by Tedgui showed that pericardial levels of 8-iso-prostaglandin F2alpha was associated with severity of HF ^[44]. The study by Chopra et al. investigated plasma lipid peroxides (MDA) in congestive HF patients and found an inverse correlation between MDA and left ventricular ejection fraction ^[45].

2.3. Oxidative Stress and Atherosclerosis

Atherosclerosis is the underlying pathology of ischemia heart diseases, stroke and peripheral artery diseases. Oxidative stress is essential for the pathological progress of atherosclerosis. Development of atherosclerotic plaques will decrease the oxygen supply which is the basis of many kinds of cardiovascular diseases ^[46]. Atherosclerosis is initiated by the injury of endothelial cells, followed by the infiltration and accumulation of oxidized low-density lipoprotein (ox-LDL) cholesterol to the subendothelial space. At the same time, leukocytes migrate to the subendothelial space. Monocytes-originated macrophages engulf ox-LDL to form foam cells ^[47]. NOX, Xo, mitochondrial enzymes are mainly responsible for the production of ROS in atherosclerosis ^[48]. NOX1 ^[49] and NOX4 ^[50] are detected in vascular smooth muscle cells (VSMCs). In comparison, NOX2 ^[51], NOX4 ^[52], and Xo ^[53] are found in endothelial cells.

Oxidative stress regulates the pathophysiology of atherosclerosis at all stages. First, oxidative stress causes endothelial dysfunction by altering endothelial signal transduction and redox-regulated transcription factors, which increase vascular endothelial permeability and catalyze leukocyte adhesion. This is considered as the initiation of plaque formation. Then, plasma LDL is recruited to the arterial wall where it is modified by oxidative stress to form ox-LDL. Ox-LDL can be taken up by macrophage to form foam cells. In addition, oxidative stress alters the expression of adhesion molecules, such as a vascular cell adhesion molecule-1, to regulate adhesion of monocytes. At the same time, increased ROS stimulate the development of the plaque by enhancing VSMCs migration and collagen deposition. Finally, oxidative stress exacerbates the stability of the plaque by releasing matrix metalloproteinase to degrade the fibrous wall ^[54][55].

Channon et al. showed the association between endothelial dysfunction and increased vascular superoxide production in human atherosclerosis ^[56]. Other study demonstrating the increase in erythrocyte TBARS with the severity of obstruction of the artery supports the potential causal relationship between oxidative stress and atherosclerosis ^[57].

2.4. Oxidative Stress and Atrial Fibrillation (AF)

AF is the most common arrhythmia in clinical practice with symptoms of irregular and rapid heart rate ^[58]. In rats, decreased plasma antioxidant capacity was associated with increased risk of AF ^[59]. Quyyumi et al. showed that there were elevated cystine level, cystine/glutathione ratio, and redox potential of glutathione (all indictive of increased oxidative stress) in AF patients ^[60]. The sources of ROS include NOX2/4 enzymes, which is upregulated in fibrillating area, and Xo ^[61].

⁺ current ^[62], L-type Ca

²⁺ current ^[63], and Ca

²⁺ leak from the sarcoplasmic reticulum (SR) ^[64]. All these result in prolonged action potential duration and reduced conduction velocity ^[65]. Furthermore, oxidative stress promotes myocardial fibrosis by facilitating the deposition of collagen ^[66]. The myocardial fibrosis interferes with the electrical coupling of myocytes ^[67]. Finally, oxidative stress may cause AF by regulating iron current associated proteins, DNA and post-translational modifications. Angiotensin II and hypoxia result in Na

⁺

⁺

²⁺

⁺

²⁺ control protein located in the SR ^[68][69].