Ovariectomy augments pressure overload-induced hypertrophy associated with changes in Akt and nitric oxide synthase signaling pathways in female rats

Abstract

Bhuiyan MS, Shioda N, Fukunaga K. Ovariectomy augments pressure overload-induced hypertrophy associated with changes in Akt and nitric oxide synthase signaling pathways in female rats. Am J Physiol Endocrinol Metab 293: E1606-E1614, 2007. First published September 18, 2007; doi:10.1152/ajpendo.00246.2007.-To elucidate the molecular mechanism underlying estrogen-mediated cardioprotection in left ventricular (LV) hypertrophy and remodeling, we analyzed myocardial hypertrophy as well as cardiac function and hypertrophyrelated protein expression in ovariectomized, aortic-banded rats. Wistar rats subjected to bilateral ovariectomy (OVX) were further treated with abdominal aortic stenosis. Effects on LV morphology and function were assessed using echocardiography, and expression of protein levels was determined by Western blot analysis. The heartto-body weight ratio was most significantly increased in the OVXpressure overload (PO) group compared with the OVX group and in the PO group compared with sham. The LV weight-to-body weight ratio was also significantly increased in the OVX-PO group compared with the OVX group and in the PO group compared with sham. The most significant increases in LV end diastolic pressure, LV developed pressure, and Ϯdp/dtmax were observed in the OVX-PO group compared with the OVX group and represent compensatory phenotypes against hypertrophy. Both endothelial nitric oxide (eNOS) synthase expression and activity was markedly reduced in the OVX-PO group, and protein kinase B (Akt) activity was largely attenuated. Marked breakdown of dystrophin was also seen in hearts of OVX-PO groups. Finally, significantly increased mortality was observed in the OVX-PO group following chronic isoproterenol administration. Our results demonstrate that rats subjected to ovariectomy are unable to compensate for hypertrophy, showed deteriorated heart function, and demonstrated increased mortality. Simultaneous impairment of eNOS and Akt activities and reduced dystrophin by ovariectomy likely contribute to cardiac decompensation during PO-induced hypertrophy in ovariectomized rats. estrogen; myocardial hypertrophy; nitric oxide synthase EPIDEMIOLOGICAL STUDIES SHOW that the incidence of cardiovascular disease is higher in men than in premenopausal women but increases in postmenopausal women (10). Sex differences in left ventricular (LV) hypertrophy and remodeling have also been observed in aging and pressure-overloaded human hearts (4). It is suggested that, because of reduced estrogen levels after menopause, women lose an important cardiovascular protective mechanism and are at greater risk of developing hypertension (1). Moreover, estrogen has multiple protective effects on the cardiovascular system (27). However, the role of estrogen in development of cardiac hypertrophy is poorly understood. Most animal models of heart failure indicate that females resist cardiac contractile dysfunction (8,11,34). The relationship of sex and hypertrophy-induced heart failure is complex and depends on the model/etiology of hy...

Activation of Endothelial Nitric Oxide Synthase by a Vanadium Compound Ameliorates Pressure Overload-Induced Cardiac Injury in Ovariectomized Rats

“…Consistent with our previous observation, 7 LV end-diastolic pressure was significantly increased in the OVX-PO group (PϽ0.001 versus OVX) compared with the OVX group. VO(OPT) treatment dose-dependently restored elevated LV end-diastolic pressure (PϽ0.001 versus OVX-PO for 1.25 mg and PϽ0.001 versus OVX-PO for 2.50 mg of vanadium; Figure 2C).…”

“…VO(OPT) treatment (2.50 mg of vanadium per kg) slightly decreased MABP in sham rats, but a significant decrease in MABP was observed in OVX rats ( Figure S2B). Consistent with a previous observation, 7 OVX-PO treatment significantly increases both in HR (PϽ0.01 versus OVX; Figure 2A) and in MABP (PϽ0.01 versus OVX; Figure 2B) compared with OVX rats. VO(OPT) treatment dose-dependently and significantly reduced HR (PϽ0.05 versus OVX-PO for 1.25 mg and PϽ0.05 versus OVX-PO for 2.50 mg of vanadium; Figure 2A) and MABP (PϽ0.05 versus OVX-PO for 1.25 mg and PϽ0.001 versus OVX-PO for 2.50 mg of vanadium; Figure 2B).…”

“…Consistent with our previous observation, LV weight (PϽ0.01 versus OVX) and LW (PϽ0.001 vs OVX) significantly increased in the OVX pressure overloaded (OVX-PO) group compared with the OVX group, without significant changes in right ventricle weight. 7 Treatment with VO(OPT) (2.50 mg of vanadium per kg, PO) on the sham and OVX rats had no effect on the morphometric parameters (Table S2). Treatment with VO(OPT) significantly and dose-dependently decreased the elevated LV weights and LWs.…”

“…6 We have also reported that pressure overload (PO)-induced hypertrophy in ovariectomized (OVX) female rats markedly reduces both endothelial NO synthase (eNOS) protein expression and its activity with concomitantly marked reduced Akt activity. 7 Inhibition of eNOS induces myocardial hypertrophy in rats. 8 Likewise, NO has antihypertrophic effects, thereby inhibiting cardiac remodeling.…”

“…7 To observe the cardioprotective effect of the Akt activator VO(OPT) in the hypertrophy-induced cardiac remodeling, we used the OVX PO-induced hypertrophy model, because that model causes reproducible hypertrophy with the severe impairment of Akt and eNOS signaling. 7 We also defined the molecular mechanism underlying VO(OPT)-mediated cardioprotection in LV hypertrophy and its remodeling. We especially focused on VO(OPT)-mediated activation of the myocardial Akt and eNOS signaling after PO-induced hypertrophy.…”