Aromatase transgenic upregulation modulates basal cardiac performance and the response to ischemic stress in male mice

Abstract

Estrogen in females is conventionally considered a cardioprotective influence, but a role for estrogen in male cardioprotection has yet to be defined. Estrogen biosynthesis from testosterone is regulated by aromatase. Aromatase has recently been shown to be expressed in the adult heart, although little is known about its involvement in the regulation of myocardial function and stress responses. The goal of this study was to determine whether upregulation of tissue aromatase expression could improve ischemic resilience in male hearts. Isolated hearts from male transgenic aromatase-overexpressing (AROM(+); high estrogen, low testosterone) mice and wild-type (WT) mice (12 wk) were Langendorff perfused and subjected to ischemia-reperfusion (25 min ischemia and 60 min of reperfusion). Basal systolic function was lower in AROM(+) hearts (dP/dtmax: 4,121 ± 255 vs. 4,992 ± 283 mmHg/s, P < 0.05) and associated with augmented Akt phosphorylation, consistent with a suppressor action of estrogen on contractility. Ischemic contracture was attenuated in AROM(+) hearts (43 ± 3 vs. 55 ± 4 mmHg, P < 0.05), yet AROM(+) hearts were more arrhythmic in early reperfusion. At the end of 60 min of reperfusion, AROM(+) systolic functional recovery was lower (left ventricular developed pressure: 39 ± 6 vs. 56 ± 5 %basal, P < 0.05) and diastolic dysfunction was accentuated (36 ± 4 vs. 24 ± 2 mmHg, P < 0.05). This is the first study to show that in vivo aromatase upregulation modulates basal cardiac performance and the response to ischemic stress. These data suggest that while chronic exposure to enhanced estrogenic influence may have benefits in limiting ischemic contracture severity, acute functional recovery in reperfusion is compromised. A temporally targeted, tissue-specific intervention combining aromatase treatment with inotropic support may offer therapeutic potential for men and women.

Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters

“…Although E-4031 10 mg/kg BW showed strong bradycardia (Table 2), aromatase knockout significantly decreased E-4031-induced QT C prolongation, indicating that ablation of endogenous estrogen affects E-4031 sensitivity. Recent data depict the importance of aromatase expression in the heart, which shows protective effects on ischemic myocardial cells and coronary vasculature damage (Bell et al, 2014;Jazbutyte et al, 2012).…”

Molecular pathways of oestrogen receptors and β‐adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

“…However, in other studies, no change was observed in the expression of NCX expression in both oestrogen treatment and OVX animals . Although oestrogen decreased the expression of PLB, and OVX increased its expression, no change in expression was found in other reports . On the other hand, oestrogen downregulated the RyR expression, while in other reports both OVX and oestrogen treatments had no effect on RyR expression .…”

Brain aromatase modulates cardiac functions in embryonic zebrafish

“…Furthermore, treatment of E 2 and ERα attenuated isoproterenol-induced cardiac hypertrophy in H9c2 cells [9], indicating beneficial action of E 2 -induced cardioprotection. Moreover, overexpression of Aro improved functional recovery post-ischaemia in mice [10]. Although gonadal tissue is the main site for E 2 synthesis, locally E 2 production in extragonadal tissues such as heart and brain likely has a specific role on these organs.…”