Backgrounds/Aim
Male and female hearts have many structural and functional differences. Here, we investigated the role of estrogen (E2) in the mechanisms of sex differences in contraction through the cAMP-L-type Ca
2+
channel pathway in adult mice left ventricular (LV) apical myocytes at basal and stress state.
Methods
Isolated LV apical myocytes from male, female (Sham) and ovariectomised mice (OVX) were used to investigate contractility, Ca
2+
transients and L-type Ca
2+
channel (LTCC) function. The levels of β
2
AR, intracellular cAMP, phosphodiesterase (PDE 3 and PDE 4), RyR2, PLB, SLN, and SERCA2a were compared among the experimental groups.
Results
We found that (1) intracellular cAMP,
I
CaL
density, contraction and Ca
2+
transient amplitudes were larger in Sham and OVX + E2 myocytes compared to male and OVX. (2) The
mRNA
expression of PDE 3 and 4 were lower in Sham and OVX + E2 groups compared with male and OVX groups. Treatment of myocytes with IBMX (100 μM) increased contraction and Ca
2+
transient amplitude in both sexes and canceled differences between them. (3) β
2
AR-mediated stress decreased cAMP concentration and peak contraction and Ca
2+
transient amplitude only in male and OVX groups but not in Sham or OVX + E2 groups suggesting a cardioprotective role of E2 in female mice. (4) Pretreatment of OVX myocytes with GPR30 antagonist G15 (100 nM) abolished the effects of E2, but ERα and ERβ antagonist ICI 182,780 (1 μM) did not. Moreover, activation of GPR30 with G1 (100 nM) replicated the effects of E2 on cAMP, contraction and Ca
2+
transient amplitudes suggesting that the acute effects of E2 were mediated by GPR30 via non-genomic signaling. (5)
mRNA
expression of RyR2 was higher in myocytes from Sham than those of male while PLB and SLN were higher in male than Sham but no sex differences were observed in the
mRNA
of SERCA2a.
Conclusion
Collectively, these results demonstrate that E2 modulates the expression of genes related to the cAMP-LTCC pathway and contributes to sex differences in cardiac contraction and responses to stress. We also show that estrogen confers cardioprotection against cardiac stress by non-genomic acute signaling via GPR30.
Cardiovascular diseases (CVDs) characterized by sex–gender differences remain a leading cause of death globally. Hence, it is imperative to understand the underlying mechanisms of CVDs pathogenesis and the possible factors influencing the sex–gender disparities in clinical demographics. Attempts to elucidate the underlying mechanisms over the recent decades have suggested the mechanistic roles of estrogen in modulating cardioprotective and immunoregulatory effect as a factor for the observed differences in the incidence of CVDs among premenopausal and post-menopausal women and men. This review from a pathomechanical perspective aims at illustrating the roles of estrogen (E2) in the modulation of stimuli signaling in the heart during chronic catecholamine stress (CCS). The probable mechanism employed by E2 to decrease the incidence of hypertension, coronary heart disease, and pathological cardiac hypertrophy in premenopausal women are discussed. Initially, signaling via estrogen receptors and β-adrenergic receptors (βARs) during physiological state and CCS were summarized. By reconciling the impact of estrogen deficiency and hyperstimulation of βARs, the discussions were centered on their implications in disruption of nitric oxide synthesis, dysregulation of lipid profiles, and upregulation of nuclear factor of activated T cells, which induces the aforementioned CVDs, respectively. Finally, updates on E2 therapies for maintaining cardiac health during menopause and suggestions for the advancement treatments were highlighted.
Due to its reversible nature, Takotsubo cardiomyopathy (TTC) is considered an intriguing and fascinating cardiovascular disease characterized by a transient wall motion abnormality of the left ventricle, affecting more than one coronary artery territory, often in a circumferential apical distribution. Takotsubo cardiomyopathy was discovered by a Japanese cardiovascular expert and classified as acquired primary cardiomyopathy by the American Heart Association (AHA) in 1990 and 2006, respectively. Regardless of the extensive research efforts, its pathophysiology is still unclear; therefore, there are no well-established guidelines specifically for treating and managing TTC patients. Increasing evidence suggests that sympatho-adrenergic stimulation is strongly associated with the pathogenesis of this disease. Under acute stressful conditions, the hyperstimulation of beta-adrenergic receptors (β-ARs) resulting from excessive release of catecholamines induces intracellular kinases capable of phosphorylating and activating “A Disintegrin and Metalloprotease 17” (ADAM17), a type-I transmembrane protease that plays a central role in acute myocardial inflammation and metabolic lipids dysregulation which are the main hallmarks of TTC. However, our understanding of this is limited; hence this concise review provides a comprehensive insight into the key role of ADAM17 in acute myocardial inflammation and metabolic lipids dysregulation during acute stress. Also, how the synergy of ADAM17-induced acute inflammation and lipids dysregulation causes TTC is explained. Finally, potential therapeutic targets for TTC are also discussed.
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