Invited Article
Sex differences in eicosanoid formation and metabolism: A possible mediator of sex discrepancies in cardiovascular diseases

https://doi.org/10.1016/j.pharmthera.2021.108046Get rights and content

Abstract

Arachidonic acid is metabolized by cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes to produce prostaglandins, leukotrienes, epoxyeicosatrienoic acids (EETs), and hydroxyeicosatetraenoic acids (HETEs), along with other eicosanoids. Eicosanoids have important physiological and pathological roles in the body, including the cardiovascular system. Evidence from several experimental and clinical studies indicates differences in eicosanoid levels, as well as in the activity or expression levels of their synthesizing and metabolizing enzymes between males and females. In addition, there is a clear state of gender specificity in cardiovascular diseases (CVD), which tend to be more common in men compared to women, and their risk increases significantly in postmenopausal women compared to younger women. This could be largely attributed to sex hormones, as androgens exert detrimental effects on the heart and blood vessels, whereas estrogen exhibits cardioprotective effects. Many of androgen and estrogen effects on the cardiovascular system are mediated by eicosanoids. For example, androgens increase the levels of cardiotoxic eicosanoids like 20-HETE, while estrogens increase the levels of cardioprotective EETs. Thus, sex differences in eicosanoid levels in the cardiovascular system could be an important underlying mechanism for the different effects of sex hormones and the differences in CVD between males and females. Understanding the role of eicosanoids in these differences can help improve the management of CVD.

Introduction

Arachidonic acid (AA) is an omega-6 polyunsaturated fatty acid (PUFA) that is found abundantly in the human cell membrane phospholipid bilayer. The chemical structure of AA involves 20 carbon atoms and four cis double bonds; hence its chemical name is all-cis-5,8,11,14-eicosatetraenoic acid. Due to their 20-carbon-atom length, AA and its derivatives are known as eicosanoids, as “eicos” in Greek means the number 20 (Hanna & Hafez, 2018).

Eicosanoids, including pro-inflammatory prostaglandins (PGs), leukotrienes (LTs), and hydroxyeicosatetraenoic acids (HETEs), as well as anti-inflammatory epoxyeicosatrienoic acids (EETs) and lipoxins (LXs), are all bioactive oxygenated AA metabolites that act as local hormones and signaling molecules. Eicosanoids have several important biological functions such as maintenance of homeostasis, blood pressure modulation, and regulation of immune responses (Harizi, Corcuff, & Gualde, 2008). Despite their important physiological functions, when overexpressed, eicosanoids can cause pain, fever, and inflammation, and they are implicated in several pathophysiological states including inflammatory and autoimmune diseases and cancers (Akaogi, Nozaki, Satoh, & Yamada, 2006; Wan & Wu, 2007; Wang et al., 2004).

Eicosanoids and their signaling pathways also play an important role in cardiovascular health and diseases, including hypertension, cardiac hypertrophy, and ischemic heart diseases (Jenkins, Cedars, & Gross, 2009). According to the World Health Organization, cardiovascular diseases (CVD) remain the leading cause of mortality worldwide (Cardiovascular Diseases, n.d.). In Canada, CVD constitute an enormous economic and health burden, and account for nearly one third of the total deaths each year (Manuel, Leung, Nguyen, Tanuseputro, & Johansen, 2003; Tarride et al., 2009).

A substantial amount of evidence indicates sex-specific differences in the incidence and the outcomes of different CVD (Regitz-Zagrosek & Kararigas, 2017). Moreover, nearly 60 years ago, attention was directed to the possible modulatory effect of sex on eicosanoid synthesis and levels (Monsen, Okey, & Lyman, 1962). Several experimental and clinical studies since then have demonstrated sex discrepancies in the levels of different eicosanoids as well as the activity or levels of their respective synthesizing enzymes in different organs, including the heart and blood vessels (Muller et al., 2007; Pace, Sautebin, & Werz, 2017).

The exact mechanisms underlying sex differences in CVD are not fully understood, although they could be largely attributed to genetic differences and hormonal factors (Regitz-Zagrosek & Kararigas, 2017). Sex hormones are known to play an important role in CVD as they have significant effects on endothelial function and renin-angiotensin-aldosterone system (Boese, Kim, Yin, Lee, & Hamblin, 2017; dos Santos, da Silva, Ribeiro, & Stefanon, 2014). However, differences in eicosanoid formation and metabolic pathways in the cardiovascular system (CVS) between males and females could also be an important player in sex hormone effects and in sex-specific differences in CVD (von Jeinsen et al., 2017). Elucidating the role of eicosanoids in these sex differences could be a step towards a better understanding of CVD pathophysiology, the development of more optimized and effective treatments, and thus lowering the disease burden. Therefore, in this review, we outline the role of eicosanoids in cardiovascular health and diseases, the reported sex differences in eicosanoid formation pathways in different organs, including the CVS, from experimental and clinical studies, and the possible underlying mechanisms for these differences.

Section snippets

Eicosanoid formation pathways

The release of AA from the cellular phospholipid depot is catalyzed by intracellular phospholipases such as phospholipase A2 (PLA2), and is driven by multiple cellular signals such as inflammation (Brash, 2001). Subsequently, released AA is subject to oxidative metabolism by several enzymes, namely cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes, generating multiple bioactive eicosanoids (Fig. 1) (Sonnweber, Pizzini, Nairz, Weiss, & Tancevski, 2018).

The two mammalian

Role of eicosanoids in cardiovascular homeostasis and diseases

In general, AA metabolism plays an important role in human health, and is especially important for the cardiovascular health and homeostasis (Tallima & El Ridi, 2018). On the cellular level, AA is important for the cell membrane flexibility and fluidity and acts as an inflammatory intermediate. AA also induces vasodilatation, and plays an important role in the modulation of sodium channels in the heart, which in turn affect cardiac excitability (Brash, 2001; Tallima & El Ridi, 2018). It was

Sex differences in eicosanoid formation pathways in cardiovascular diseases

There is a clear gender discrepancy in the incidence, outcome, and manifestations of different CVD. In general, males demonstrate a higher risk of developing different types of CVD, such as hypertension, ischemic heart diseases, and cardiac hypertrophy compared to females of the same age, and post-menopausal women show a higher risk than women before menopause (Vitale, Mendelsohn, & Rosano, 2009). This sex discrepancy could be attributed to hormonal and genetic factors. However, given the

Androgens

Sex hormones play important roles in the cardiovascular health and diseases (Boese et al., 2017; dos Santos et al., 2014). The greater risk of CVD in men could be attributed, at least in part, to the detrimental cardiovascular effects of androgens (Schenck-Gustafsson et al., 2011; Yanes & Reckelhoff, 2011). Several animal studies showed that testosterone is involved in the development of endothelial dysfunction and hypertension, and that gonadectomy or androgen receptor blockade could

Conclusion

CVD remain the main cause of death worldwide. In general, CVD are more common in males than in females, and this might be attributed to the detrimental effects of androgens, and the beneficial effects of estrogens on the cardiovascular health. Eicosanoids are AA metabolites formed by COX, LOX, and CYP enzymes, which play important roles in cardiovascular homeostasis and diseases. A huge amount of evidence now indicates gender differences in the levels of different eicosanoids and the expression

Declaration of Competing Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

This work was supported by a grant from the Canadian Institutes of Health Research (CIHR PS 168846) to A.O.S.E.

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