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

Abstract

Abstract-We here investigated the effect of bis(1-oxy-2-pyridinethiolato) oxovanadium (IV), [VO(OPT)], against myocardial hypertrophy and cardiac functional recovery in pressure overload-induced hypertrophy in ovariectomized female rats and defined mechanisms underlying its cardioprotective action. Wistar rats subjected to bilateral ovariectomy were further treated with abdominal aortic stenosis. VO(OPT) (containing 1.25 and 2.50 mg of vanadium per kg) was administered orally once a day for 14 days starting from 2 weeks after aortic banding. Treatment with VO(OPT) significantly inhibited pressure overload-induced increase both in the heart weight:body weight ratio and the lung weight:body weight ratio. VO(OPT) also attenuated hypertrophy-induced impaired left ventricular end-diastolic pressure, left ventricular developed pressure, and left ventricular contractility (Ϯdp/dt max ). VO(OPT) treatment significantly restored pressure overload-induced impaired endothelial NO synthase activity with concomitant increased phosphorylation of endothelial NO synthase (Ser1179). Moreover, VO(OPT) treatment significantly restored pressure overload-induced reduced Akt activity, as indicated by increased phosphorylation at Ser473 and at Thr308. Treatment with VO(OPT) also secondarily inhibited calpastatin and dystrophin breakdown and decreased myosin light chain phosphorylation. Finally, VO(OPT) treatment significantly attenuated mortality after repeated isoproterenol administration in pressure overloaded-ovariectomized rats. Taken together, VO(OPT) attenuates cardiac myocytes hypertrophy in vivo in pressure overload-induced hypertrophy in ovariectomized rats and prevents the process from hypertrophy to heart failure. These effects are mediated by inhibition of calpastatin and dystrophin breakdown in addition to increased Akt and endothelial NO synthase activities. Key Words: myocardial hypertrophy Ⅲ protein kinase B (Akt) Ⅲ endothelial nitric oxide synthase (eNOS) Ⅲ ovariectomy Ⅲ dystrophin L eft ventricular (LV) hypertrophy is an independent risk factor for the development of heart failure. 1 Although LV hypertrophy is an adaptive response to pressure and volume overload, this process becomes maladaptive without drug therapy. The pathological cardiac hypertrophy, in turn, triggers the development of heart failure. 2 The search for novel drug treatment has directed attention to cardiac hypertrophy as cardioprotection. 2 Signaling through the phosphatidylinositol 3-kinase/Akt pathway is important for the physiological growth and inhibition of pathological hypertrophy. 3-5 Moreover, physiological hypertrophy induced by exercise training also requires the activation of myocardial Akt. By contrast, pathological hypertrophies induced by pressure overload cause an inactivation of the Akt signal pathway. 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 Ak...

Cardioprotection by Vanadium Compounds Targeting Akt-Mediated Signaling

“…Until now, four vanadium compounds, namely, sodium orthovanadate (OV) (42,43); vanadyl sulfate (VS) (20,22,30); bis(maltolato)oxovanadium (IV) [BMOV] (21,44,45); and VO(OPT) (18,19,28), have been found to have cardioprotective effects in different heart injury models (Fig. 1).…”

“…Like other cardioprotective vanadium compounds (30,42,43), VO(OPT) is a potent Akt activator both in vitro (38) and in vivo (18,19,28,47,48). In vitro studies using 3T3-L1 mouse adipocytes demonstrate that treatment with VO(OPT) increased the tyrosine phosphorylation of proteins including the β-subunit of the insulin receptor and insulin receptor substrate-1 (38,48), suggesting that VO(OPT) can inhibit PTPase.…”

“…We recently introduced a novel heart injury model using ovariectomized (OVX) pressure overloaded (PO) female rats, which is attractive for testing cardioprotective drugs in hypertension-induced cardiac injury in postmenopausal women (29). The most relevant phenomenon in the heart of OVX-PO female rats was impairment of Akt and endothelial nitric oxidase synthase (eNOS) signaling (28,29). Lack of estrogen by ovariectomy and pressure overload led to reduction of Akt activity (29).…”

“…To develop a novel therapeutic drug to protect cardiomyocytes from heart diseases, we selected a novel vanadyl (IV) compound having the VO 2+ chelate: bis(1-oxy-2-pyridinethiolato) oxovanadium (IV) [VO(OPT)], which is a potent activator of the Akt signaling pathway both in vivo and in vitro (38 -41). We previously documented that VO(OPT)-mediated Akt activation elicited cardioprotection in ischemia /reperfusion-induced injury in rats (18,19) and myocardial pressure overload-induced hypertrophy in ovariectomized female rats along with cardiac functional recovery (28). Vanadium compounds inhibit protein tyrosine phosphatases (38,39) and promote an increase in protein tyrosine phosphorylation, leading to the upregulation of Akt (38).…”

Vascular Endothelial σ₁-Receptor Stimulation With SA4503 Rescues Aortic Relaxation via Akt/eNOS Signaling in Ovariectomized Rats With Aortic Banding

“…18, 19 Adequate depth of anesthesia was σ1-Receptor Stimulation Rescues Aortic Dysfunction (1.0 mg/kg) restored the vascular remodeling observed in OVX-PO rats. Co-administration of NE-100 with SA4503 eliminated its ameliorating effect on vascular remodeling.…”