The prevalence of heart failure is about the same for both males and females 6. This is because even though more males are diagnosed with heart failure, the number of males and females living with heart failure is similar as women with heart failure usually have a lower mortality rate than men.
There is also a difference in the most common type of heart failure in men and women: diastolic heart failure occurs more often in women, whereas systolic heart failure occurs more often in men 6.
Hypertension, cardiac hypertrophy and ischaemia—reperfusion injury are three other major cardiovascular conditions where gender differences are present. Young adult women are less likely to develop hypertension than men Also, animal studies have shown that males develop an earlier and more severe hypertension than females 12 - Males are also shown to have increased cardiac hypertrophy compared to females 15 , 16 Fig. Females are also more likely to have relatively preserved left ventricular function In addition to reduced hypertrophy, studies have also shown that females have reduced ischaemia—reperfusion injury 15 , 17 Fig.
The beneficial outcome in ischaemia—reperfusion injury in females may be due to the effect of estrogen.
Elevated calcium levels increase ischaemia—reperfusion injury, and estrogen may lower the calcium levels before ischaemia leading to less injury in females In addition to cardiovascular diseases themselves, there is also a link between several cardiovascular disease risk factors and gender. Thus, diabetic women have an even higher risk of developing heart disease compared to diabetic men. Higher HDL levels in female would lead to a lower risk of cardiovascular diseases. While elevated triglyceride levels are a risk factor for both men and women, elevated triglycerides levels increase the CAD risk more in women than in men There are also differences in risk factors before and after menopause, suggesting a possible role of estrogen.
These changes in LDL and total cholesterol levels may actually begin prior to menopause in the perimenopausal period. One study has shown that increases in total cholesterol and LDL levels are significant around the time of the last menstrual period and these increases are greater than the changes seen before or after the last menstrual period The menopausal transition therefore may be a crucial time when lipid levels increase in females prior to the actual onset of menopause.
The question then remains whether the presence of estrogen could explain the gender differences in various cardiovascular diseases or whether other mechanisms are involved. Sex hormones including estrogen are present globally with their receptors in the heart 6 , suggesting that the sex hormones may exert their effects on cardiovascular system by affecting the heart itself.
In animal models, estrogen has been shown to improve heart function and decrease the severity of injuries 6. A comprehensive systematic review revealed that HRT had no cardiovascular benefit and that estrogen therapy alone significantly increased the risk of stroke when compared to placebo Therefore, the role of estrogen and its effect on the cardiovascular system are still unclear. Further studies are needed to identify other mechanism s. Oxidative stress is a condition that occurs when the rate of reactive oxygen species ROS formation exceeds the rate of the antioxidant defence system However, at times during disease states such as inflammation or infection and environmental stress e.
Chlorinative stress in age-related diseases: a literature review
UV or heat exposure or ionizing radiation, ROS levels could increase dramatically and may result in significant damage to cellular structures Oxidative stress is considered an important mechanism for the development of cardiovascular diseases 4 , 5. Hyperlipidaemia and diabetes in particular are both associated with increased oxidative stress, which may lead to the development of atherosclerosis 4 , 5.
In addition to cardiovascular diseases, other diseases and ageing are accompanied with oxidative protein damage Because oxidative stress plays such an important role in various diseases, it is important to study any gender differences associated with oxidative stress. Hydrogen peroxide is a relatively stable ROS that is formed as a product of the free radical superoxide by the enzyme superoxide dismutase SOD The production of hydrogen peroxide is dramatically increased during the oxidative burst in inflammatory conditions, including the response to lipopolysaccharides both in vitro and in vivo 33 - In addition to ROS, a number of reactive nitrogen species including nitric oxide and peroxynitrite are also produced in vascular cells Under normal conditions, cells are protected from ROS by antioxidant defence mechanisms including enzymes such as SOD, catalase and glutathione peroxidase GPx As mentioned previously, SOD rapidly catalyses the conversion of superoxide to hydrogen peroxide.
Hydrogen peroxide is metabolized to oxygen and water by either catalase or GPx 31 , 32 Fig. These antioxidant enzymes are crucial for the normal redox balance in cells. When this redox balance is interrupted, and more ROS are present than the antioxidant defence system can handle, oxidative stress and cell damage result. As discussed previously, the association between gender and oxidative stress is important because oxidative stress is implicated in many diseases that present differently in males and females.
This section of the review will focus on the relationship between gender and oxidative stress Table 2. It was reported that oxidative stress was higher in male rats than female rats Another study showed that in vivo biomarkers of oxidative stress were higher in young men than in women of the same age Similarly, it was observed that ROS production was higher in the vascular cells from males than in the cells from females In addition, clinical and experimental data suggested a greater antioxidant potential in females over males These studies indicate that there is an apparent association between gender and oxidative stress, where women seem to be less susceptible to oxidative stress.
For oxidative stress to occur, there needs to be an imbalance between ROS production and the antioxidant defence system. These enzymes are present in multiple tissues in the body. In regard to SOD, there is no uniform consensus on gender differences, but it has been suggested that there may be a difference in certain tissues. It was reported that brain and lung SOD activity levels were higher in female mice, but there was no significant difference in SOD activity levels between male and female mice in the kidney or heart In another study, female rats were found to have higher SOD activity levels in the heart than the males Interestingly, the SOD activity levels in both male and female rats were significantly decreased after castration compared to their respective controls 37 , suggesting that there could be an association between sex hormones and SOD activity levels.
However, some studies showed no difference in SOD activity levels between males and females; thus, some discrepancy regarding the association of SOD activity and gender still remains 38 , Catalase activity levels were found to be the same between genders in the brain, heart, lung and heart, but higher in the female kidney However, some studies showed no difference in catalase activity levels between males and females 37 , 38 , These data suggest that catalase activity and thus hydrogen peroxide degradation may not be affected by gender and sex hormones.
Several studies demonstrated that GPx activities were lower in females compared to males 37 , 38 , After castration, there was no significant change in GPx activity levels, suggesting that GPx might not be influenced by sex hormones Glutathione peroxidase was the only antioxidant enzyme that consistently showed a gender bias across several studies. The fact that GPx levels were lower in females seemed counterintuitive, as females were believed to be less susceptible to oxidative stress than males. These observations suggested that other mechanism s had to be present in females to overcome the lower levels of GPx.
Expression of Nox1 and Nox4 was higher in males than in females, suggesting that gender differences in superoxide formation could be due to the activity of these two subunits This was consistent with a recent finding that Nox4 levels were significantly lower in the mesenteric arteries of female rats compared to the males The above two studies were also consistent in showing that Nox2 levels did not differ between males and females 36 , Another study using pigs showed higher levels of Nox1 and Nox2 in porcine isolated coronary arteries PCA in males although Nox4 was higher in females It could be possible that higher expression of Nox subunits in men could in part explain why males exhibit higher levels of oxidative stress than females Fig.
Wong et al. At the molecular level, there have been a few studies on the differences between males and females in regard to oxidative stress and gene and protein expressions. As mentioned above, Nox1 and Nox4 expression was found to be higher in males in the basilar artery There are few studies on gender differences in gene expression, and further research is needed.
Catalase mRNA expression was not changed by surgery While there may be some differences in antioxidant enzyme activity levels between males and females as discussed previously, the greatest difference in antioxidant properties is likely due to estrogen. Estrogen acts as an antioxidant by scavenging free radicals due to the presence of a phenolic hydroxyl group The antioxidant action of estrogen could explain the gender differences with GPx. Because estrogen acts as a potential antioxidant in females, less GPx is needed in females compared to males who would not benefit from the antioxidant properties of estrogen.
Indeed, it was found that after castration, oxidative stress was higher in female rats compared to female controls, but there was no significant difference in males after castration There have been some studies that showed no correlation between estrogen levels and oxidative stress Other than being a potential antioxidant, estrogen has also been found to increase mitochondrial ROS production, which is involved in cell signalling pathways Clearly, estrogen has a complex role, and it is possible that its effect on oxidative stress is multifaceted.
There are many diseases associated with oxidative stress. A clear difference in gender and oxidative stress could be observed in various diseases, including autoimmune thrombocytopenia AITP , pancreatic disease, ageing, thyroid disease and some cardiovascular diseases such as CAD. Autoimmune thrombocytopenia is a bleeding disorder, and women with AITP have significantly higher levels of oxidative stress compared to both female controls and males with AITP In regard to pancreatic disease, female rats exhibit higher protection against oxidative stress and thus have a lower risk of developing insulin resistance compared to male rats In addition to these disease states, oxidative stress and gender have been shown to be associated with ageing.
The markers of oxidative protein damage are significantly higher in male rats than in female rats of the same age The rate of ROS production by mitochondria in females is also significantly lower than that of males, which has been implicated in ageing 52 , Thyroid disease is more prevalent in females, and one study found that adult female thyroids produced significantly higher amounts of hydrogen peroxide than males This same study found that Nox4 levels were 1. These observations show that the gender differences associated with oxidative stress in various disease processes could have important implications.
Further studies are needed to determine whether gender plays an important role in other disease states associated with oxidative stress. The most apparent association between oxidative stress and gender can be seen in the cardiovascular system where oxidative stress has a very prominent effect. Recent studies suggest that levels of vascular ROS may be lower in females than in males during physiological conditions One such study found that under normal conditions, the male rat aortas generated more superoxide radicals than the female aortas As mentioned previously, the enzyme SOD rapidly converts superoxide to hydrogen peroxide.
There was some discrepancy as to whether SOD activity levels differed between males and females, with several studies showing no difference. It is therefore less likely that the difference in superoxide levels is due to SOD activity. Estrogen therefore may contribute to the differences in superoxide levels between males and females. This same study also showed that superoxide production decreased in male Nox2 knockout mice, but not in the females, suggesting that Nox2 plays a role in mediating ROS generation in response to angiotensin II in males but not in females This subunit is connected to the angiotensin II system as angiotensin II binds to the angiotensin type I receptor, which then induces the phosphorylation of p In addition to physiological conditions, studies have been conducted to evaluate the relationship between oxidative stress and gender under pathologic conditions such as hypertension, diabetes, CAD and shock.
Male spontaneously hypertensive rats were found to have higher levels of superoxide generation than female rats Male spontaneous hypertensive rats also have lower levels of nitric oxide NO due to its degradation by superoxide, thus contributing to oxidative stress This mechanism appears to be related to sex although more research is needed to determine the exact role sex plays One study showed that mRNA expression of eNOS was increased in ovariectomized pigs compared to gonadally intact female and male pigs although there was no difference in the protein expression of eNOS Another study with diabetic rats demonstrated that eNOS mRNA expression was higher in the aorta of normal female controls compared to male controls although the mRNA level was the same in males and females with diabetes This same study found that Nox subunits also played a role in diabetes.
Han et al. This may explain why the female aorta is predisposed to injury early in diabetes.
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