Oxidative Stress Links Aging-Associated Cardiovascular Diseases and Prostatic Diseases

The incidence of chronic aging-associated diseases, especially cardiovascular and prostatic diseases, is increasing with the aging of society. Evidence indicates that cardiovascular diseases usually coexist with prostatic diseases or increase its risk, while the pathological mechanisms of these diseases are unknown. Oxidative stress plays an important role in the development of both cardiovascular and prostatic diseases. The levels of oxidative stress biomarkers are higher in patients with cardiovascular diseases, and these also contribute to the development of prostatic diseases, suggesting cardiovascular diseases may increase the risk of prostatic diseases via oxidative stress. This review summarizes the role of oxidative stress in cardiovascular and prostatic diseases and also focuses on the main shared pathways underlying these diseases, in order to provide potential prevention and treatment targets.


Introduction
Cardiovascular diseases (CVDs), including hypertension, coronary heart disease (CHD), cerebrovascular disease, and heart failure, are the major cause of death globally. In the period from 1990 to 2019, the prevalence of total CVD nearly doubled from 271 million to 523 million cases, and the number of CVD deaths steadily increased from 12.1 million to 18.6 million [1]. In 2019, ischaemic heart disease was one of the top-ranked causes of disability adjusted life years (DALYs) in both the 50-74-year and 75-years-and-older age groups [2]. According to World Health Organization (WHO) statistics, almost 23.6 million people will die from CVDs by 2030. Benign prostatic hyperplasia (BPH) and prostate cancer are also aging-associated diseases. The incidence rate of BPH increases with age affecting about 50% of men over 50 years, increasing to 80% when they reach 80 or above [3,4]. There is also an increased incidence in prostate cancer cases from 940,000 in 2007 to 1.3 million in 2017 [5], and the age-standardized incidence of prostate cancer in China also rose by 2.75% from 1990 to 2017 [6]. Aging clearly plays an important role in CVDs (such as hypertension and CHD) and prostatic diseases (prostate cancer and BPH).
The current evidence suggests that CVDs usually coexist with prostatic diseases or increase its risk, and there are 13 related clinical studies showing CVD as a risk factor for prostatic diseases (see Table 1); however, whether there is a causal relationship between them is still controversial. Numerous studies have reported that oxidative stress can promote the occurrence and development of both prostatic diseases and CVDs [7][8][9][10]; hence, to summarize its role in these two diseases can provide information for seeking prevention and potential therapeutic targets.

Oxidative Stress
The concept of oxidative stress originated from human understanding of aging. In 1956, Professor Harman first proposed the theory of free radical aging. In 1990, Professor Sohal pointed out the flaws of this theory and put forward the concept of oxidative stress for the first time [24,25]. 2 Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity
Oxidative stress is a situation where the balance of oxidative systems and antioxidative systems in vivo is changed in favour of the former [26,27]. Oxidants are regulators of normal cellular function, but when the production of reactive oxygen species (ROS) exceeds the scavenging capacity, the oxidation and antioxidant systems will be unbalanced, causing damage to the tissues and cells; this phenomenon is called oxidative damage [28][29][30]. ROS includes superoxide anion (O2 •-), hydroxyl radical (•OH), and hydrogen peroxide (H 2 O 2 ). To maintain the balance, there are two antioxidative systems in vivo: one is the enzyme antioxidant system, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX), and the other is the nonenzyme antioxidant system which includes vitamin C, vitamin E, glutathione, melatonin, α-lipoic acid, carotenoids, and trace elements such as copper, zinc, and selenium (SE). Figure 1 presents the oxidative stress theory and the sources of ROS and antioxidants.
2.1. Characteristics of ROS. ROS are generated by a variety of extracellular and intracellular actions ( Figure 1). The main intracellular source of ROS is the mitochondrial respiratory chain. The O2 •is the principal ROS formation which is produced by the enzymatic reaction and a nonenzymatic electron transfer reaction in cell. The enzymes that generate the superoxide include NADPH oxidase (NOX), xanthine oxidase (XO), lipoxygenase (LOX), and cyclooxygenase (COX) [31]. H 2 O 2 is produced from O2 •by enzymatic dismutation by the three isoforms of Cu/Zn/Mn SOD in intracellular. Most of the H 2 O 2 is converted to H 2 O by the catalase (CAT), glutathione peroxidase (GPX), and peroxiredoxins (PRX). H 2 O 2 can damage DNA when it is converted to a •OH through Fenton and Haber-Weiss reactions in the transition metal ions, especially iron ions (Fe +2 ). The •OH is the most toxic form of ROS which causes various types of DNA damage, lipid peroxidation, and protein modification [32]. The extracellular sources of ROS commonly included pollution, inflammation, cigarette smoke, radiation, and medication [33].
At present, accurately measuring ROS in disease is still a problem. ROS are unstable, and their half-lives are relatively short. For example, the half-life of O2 •is 10 −6 to 10 −9 seconds , and the •OH is 10 −9 seconds [34,35]. Therefore, ROS are routinely measured by biomarkers of oxidative damage, which included markers of protein damage (protein carbonyl derivatives), lipid peroxidation (malondialdehyde [

Pathophysiological Role of Oxidative Stress in CVD and Prostatic Diseases
Numerous clinical studies have indicated that oxidative stress plays a role in CVD and prostatic diseases ( Table 2). Studies have reported that the level of oxidative stress biomarkers was higher in CVD patients [37][38][39][40]. Additionally, current evidence suggests that oxidative stress is associated with the etiology and pathogenesis of the prostatic diseases [9,[41][42][43]. Hence, the phenomenon of CVD increasing the risk of prostatic diseases may be attributed to oxidative stress ( Figure 2).

Renin-Angiotensin System in CVD and Prostatic Diseases.
It is well established that the activation of renin-angiotensin system (RAS) is critically associated with the pathogenesis of hypertension and atherosclerosis [58][59][60]. Previous studies have reported the existence of local RAS in the prostate, and the overactivity of the RAS may be involved in the pathophysiology of BPH and prostate cancer [61][62][63][64]. The RAS includes angiotensinogen, renin, angiotensin conversion enzyme (ACE), angiotensin II (Ang II), and angiotensin receptors. Ang II is a biologically active peptide in the RAS, and its main effector receptor is type 1 receptor (AT 1 R) (Figure 2). The ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been successfully used as antihypertensive medication, and some studies have reported that these drugs have also been used in anticancer therapy [65,66]. A meta-analysis which included 9 cohort studies with 20267 patients suggested that the use of ACEIs/ARB may be associated with a decreased risk of prostate cancer [65]. However, another meta-analysis of observational studies did not find a significant relationship between the use of ACEIs/ARB and prostate cancer risk [67]. Although it is still controversial, ACEIs or ARBs have been used to reduce the risk of prostate cancer. One study showed that the expression level of AT 1 R mRNA was higher in prostate cancer than that in the normal human prostate, based on the data, and ACEIs or ARB may inhibit prostate cancer [68]. Another study reported that the ACEI captopril lowers the risk of prostate cancer, but it was not significant [69]. In BPH patients, a clinical study showed that the use of ARB can improve prostatic hyperplasia [70], whereas other antihypertensive drugs were not effective, which indicates that ARB could ameliorate BPH independently of decreasing blood pressure. The ARB drug Losartan could treat the BPH in spontaneously hypertensive rats (SHRs). The study showed that long-term Losartan treatment restored prostatic blood flow and reduced tissue MDA (oxidative stress marker) in SHRs [71]. These findings suggest that ARB/ACEI may also effective in prostatic diseases.
Traditionally, it has been thought that Ang II can directly achieve vasoconstriction by interacting with AT 1 R in vascular smooth muscle. Recently, a novel signalling mechanism for Ang II-induced vascular superoxide (O 2 -) formation was associated with the development of endothelial dysfunction, hypertension, and atherosclerosis. The source of this increased O 2 seemed to be membrane-bound vascular NADPH oxidases (NOXs) [72,73]. A study has also reported that angiotensin II also induced the production of ROS prostate cancer cells by upregulating the subunits of NADPH oxidase (NOX) [74]. In addition, another study has found expressions of various NOX isoforms in prostate cancer cell lines and a cross-talk between the endogenous ROS generation by NOX system and the tumorigenic potential [41]. Taken together, the ROS generated by NOX may play the central role connecting CVD and prostatic diseases.

NOX in CVD and Prostatic Diseases.
NOXs are the key enzymes of redox signalling and also the main source of ROS in vivo [75]. ROS are generated by NOX in the pathogenesis of CVD (see Figure 2). In human cells, there are seven isoforms of the NOX family proteins, which are NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2. NOX1, NOX2, and NOX5 directly generate superoxide anions. Conversely, the NOX4 produces H 2 O 2 which may be associated with its localization in the mitochondria in (i) The level of total thiol groups (TTG) and glutathione A significant difference of TTG was observed in BPH and PCa patients, and the level of glutathione was lower in PCa patients. [57] HP: hypertension; CHD: coronary heart disease; O 2 -: superoxide anion; HIAE: high-intensity aerobic exercise; LIAE: low-intensity aerobic exercise; BFE: blood flow restriction; TBARS: thiobarbituric acid-reactive substances; SOD: the enzyme activities of superoxide dismutase; GPX: glutathione peroxidase; CAT: catalase; Cu: copper; Zn: zinc; NR: not reported; BPH: benign prostatic hyperplasia; PCa: prostate cancer; TEAC: total equivalent antioxidant capacity; a the data from Macedonia; b the data from Turkey; MDA: erythrocyte malondialdehyde; NO2 − /NO3 − : nitrite/nitrate; 8-OHdG: 8-hydroxy-2′-deoxyguanosine; GST: glutathione s-transferase. 7 Oxidative Medicine and Cellular Longevity cardiomyocytes and in the endoplasmic reticulum in endothelial cells [76][77][78]. Superoxide cannot cross the membranes of these organelles. DUOX1 and DUOX2 also produce H 2 O 2 [79]. The transmembrane subunit P22 phox and NOX subtypes (NOX1, NOX2, and NOX4) make up the membrane-bound catalytic core [80]. The NOX4 activity requires P22 phox and is also regulated by POLDIP2. Of the seven NOXs, NOX1 and NOX2 play a role in immune defence [81], other NOXs act as the second messenger to participate in the regulation of cell signal pathways and maintain the stability of the intracellular environment [82].
3.2.1. NOX and CVD. The association between increased vascular ROS production and hypertension has been reported in animal models with Ang II induced via NOX activation [72]. Some recent in vitro studies have suggested a pivotal role of the NOX and its subunit p47phox in vascular oxidant stress and the blood pressure response to angiotensin II [83,84]. The previous studies have reported that the expression of mRNA in NOX1, NOX2, and NOX4 was increased in aortas from animals infused with Ang II [85,86]. In addition, the expression of NOX2, NOX4, and NOX5 was found to be upregulated by Ang II in endothelial cells [87,88], and knockout of NOX1, NOX2, and NOX4 in mice can reduce blood-pressure elevation induced by Ang II [86,89,90]. Taking together, these data suggest that activation of NOX1, NOX2, NOX4, and NOX5 play an important role in the development of Ang II-induced hypertension.
NOX2 is a major ROS source in the heart, and its activity increases after acute myocardial infarction (AMI). Compared with the normal human cardiomyocytes, the expression of NOX2 was higher in patients with AMI [91]. One study reported that the absence of NOX2 in Apoe-/-mice decreased ROS production, increased NO bioavailability, and reduced aortic atherosclerosis [92]. But Sirker et al. indicated that the overexpression of NOX2 in cardiomyocyte or endothelial cell made no difference to initial infarct size in mice with AMI at 4 weeks [93]. Vendrov et al. [94] suggest that expression of NOX4, but not NOX1 or NOX2, was correlated with increased mitochondrial oxidative stress, mitochondrial and cardiovascular dysfunction, and atherosclerosis in aged mice. The study indicated that NOX4 is a potential therapeutic target for aging-associated cardiovascular disease. The current study also demonstrated that NOX5 expression increased in patients with AMI, especially in infarctions > 12 hours [95]. In summary, the expression of NOX2, NOX4, and NOX5 plays a role in the development of coronary heart disease.

NOX and Prostatic Diseases.
Evidence has showed that the aberrant activation of NOX plays a critical role in prostate cancer growth and progression [96,97]. A recent study showed that NOX expression is directly associated with prostate cancer in mice, and when NOX was inhibited, the expression of HIF-1α in the nucleus was significantly decreased as well as a reduction in the proliferation and colony formation of prostate cancer [98]. Some studies have shown that NOX1 and its transmembrane subunit P22 phox and NOX5 are overexpressed in prostate cancer [99][100][101][102], and downregulated NOX5 expression can inhibit cell proliferation and tumor growth and induce apoptosis of prostate cancer cells [103]. In addition, studies have reported that  Figure 2: ROS generated by NOX in the pathogenesis between CVD and prostatic diseases. The renin-angiotensin system (RAS) exists in both heart and prostate; in addition, the overactivity of the RAS is found in both cardiovascular diseases (CVD) and prostatic diseases. The RAS includes angiotensinogen, renin, angiotensin conversion enzyme (ACE), angiotensin II (Ang II), and angiotensin receptors. Ang II is a biologically active peptide in RAS, and its main effector receptor is the type 1 (AT 1 R). Ang II induced the ROS by activation of the subunits of NADPH oxidase (NOX), and then, the increased ROS effects the development of CVD and prostatic diseases. Thus, NOXderived ROS signal may be a common potential target in therapeutic intervention of CVD and prostatic diseases. 8 Oxidative Medicine and Cellular Longevity various isoforms of NOX are found in prostate cancer cell lines, including NOX4, NOX2, and NOX5, which are absent in normal prostate cell lines [104,105]. An in vitro study has shown that the imbalance of redox homeostasis caused by elevated NOX4-derived ROS signal was the basis of fibroblast-tomyofibroblast differentiation in the diseased prostatic stroma, which indicates NOX4 inhibitors have potential clinical value in the prevention of BPH and prostate cancer [106]. Thus, NOX1, NOX2, NOX4, and NOX5 may be potential targets for therapeutic intervention in prostate cancer.

Conclusion
Evidence from clinical and animal studies demonstrates that CVD is associated with prostatic diseases, and oxidative stress may erect a bridge between these diseases; however, the exact mechanism of oxidative stress in CVD and prostatic diseases remains to be further elucidated. We provide a framework for future experimental and clinical studies on the role of known and yet to be discovered oxidative stress in CVD and prostatic diseases. The mechanisms and signalling processes by Ang II increased ROS production via NOX in these diseases is yet to be proved. Furthermore, NOX-derived ROS signals may be a common potential target in therapeutic intervention of CVD and prostatic diseases.

Conflicts of Interest
The authors declare that there are no conflicts of interests.