Abstract
Cardiovascular disease (CVD) is the leading cause of death in the U.S. and worldwide. Sex-related disparities have been identified in the presentation and incidence rate of CVD. Mitochondrial dysfunction plays a role in both the etiology and pathology of CVD. Recent work has suggested that the sex hormones play a role in regulating mitochondrial dynamics, metabolism, and cross talk with other organelles. Specifically, the female sex hormone, estrogen, has both a direct and an indirect role in regulating mitochondrial biogenesis via PGC-1α, dynamics through Opa1, Mfn1, Mfn2, and Drp1, as well as metabolism and redox signaling through the antioxidant response element. Furthermore, data suggests that testosterone is cardioprotective in males and may regulate mitochondrial biogenesis through PGC-1α and dynamics via Mfn1 and Drp1. These cell-signaling hubs are essential in maintaining mitochondrial integrity and cell viability, ultimately impacting CVD survival. PGC-1α also plays a crucial role in inter-organellar cross talk between the mitochondria and other organelles such as the peroxisome. This inter-organellar signaling is an avenue for ameliorating rampant ROS produced by dysregulated mitochondria and for regulating intrinsic apoptosis by modulating intracellular Ca2+ levels through interactions with the endoplasmic reticulum. There is a need for future research on the regulatory role of the sex hormones, particularly testosterone, and their cardioprotective effects. This review hopes to highlight the regulatory role of sex hormones on mitochondrial signaling and their function in the underlying disparities between men and women in CVD.
Highlights
Pathway, elevating PGC-1α and preserving mitochondrial integrity leading to decreased cardiomyocyte apoptosis, as demonstrated by rodent models (Witt et al, 2008; Wang F. et al, 2015)
The ability of both estrogen and testosterone to activate PGC-1α in cardiac tissue has been extensively studied, and it is well-established that PGC-1α regulates the transcription of dynamin-related protein-1 (Drp1), fission protein 1 (Fis1), mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), optic atrophy-1 protein (Opa1), and other important mitochondrial dynamic proteins (Table 1; Witt et al, 2008; Papanicolaou et al, 2012; Martin et al, 2014; Wang F. et al, 2015; Park et al, 2017)
There are clinical disparities in Cardiovascular disease (CVD) risk and incidence, which could be caused by known sexually dimorphic differences in cardiac cells and tissues. These differences are driven by the sex hormones—estrogen and testosterone—and the presence of their receptors ERα, ERβ, GPER and androgen receptors (ARs), which are expressed differentially in varying organ systems and cell types
Summary
Cardiovascular disease (CVD) is modulated by mitochondrial dysfunction, calcium handling, aging, etc., which are reviewed in detail in the corresponding reviews (Khoury et al, 1992; Sandstede et al, 2000; Berridge, 2003; Lou et al, 2012; Keller and Howlett, 2016; Ventura-Clapier et al, 2017; Virani et al, 2020). The metabolic differences associated with changes in hormone status—which are influenced by a plethora of factors including sex chromosomes, gene expression and regulation, and epigenetics—are key to understanding CVD disparities between men and women (Ventura-Clapier et al, 2019). To elucidate the roles of estrogen and testosterone in CVD, it is essential to understand the roles of their associated receptors, including estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), G protein coupled estrogen receptor (GPER/GCPR30), and ARs. The regulation of estrogen and androgen receptor expression is challenging to study, as they are sex-, age-, cell type-, and organelle-specific (Lizotte et al, 2009; Dart et al, 2013; Bowling et al, 2014; Hutson et al, 2019). More research is needed to determine the expression and role of GPER in preventing CVD injury
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