Cardioprotective Effect of Vanadyl Sulfate on Ischemia/Reperfusion‐Induced Injury in Rat Heart In vivo Is Mediated by Activation of Protein Kinase B and Induction of FLICE‐Inhibitory Protein

Abstract

Here we explored the mechanism of cardioprotective action of a tyrosine phosphatase inhibitor vanadyl sulfate on myocardial infarction and cardiac functional recovery in rats subjected to myocardial ischemia/reperfusion (MI/R) in vivo. Male Sprague-Dawley rats underwent 30 min heart ischemia by left coronary artery occlusion followed by 24-h reperfusion. Rats were randomized to receive either vehicle or vanadyl sulfate (1 and 5 mg/kg) intraperitoneally 0 min and 30 min after the start of reperfusion. Posttreatment with vanadyl sulfate significantly reduced the infarct size and significantly decreased the elevated left ventricular end diastolic pressure, improved left ventricular developed pressure, and left ventricular contractility (± dP/dt) after 72-h reperfusion in a dose-dependent manner. Moreover, treatment with vanadyl sulfate also significantly inhibited the apoptosis-related Caspase-3 and Caspase-9 processing, thereby elicited the antiapoptotic effect. The cardioprotective effect of vanadyl sulfate was closely associated with restoration of reduced protein kinase B (Akt) activity following MI/R injury. The recovered Akt activity correlated with increased phosphorylation of forkhead transcription factors, FKHR and FKHRL-1, thereby inhibiting apoptotic signaling. Furthermore, treatment with vanadyl sulfate significantly increased FLICE-inhibitory protein (FLIP) expression, and decreased expression of Fas ligand and Bim in cardiomyocytes. Taken together, rescue of cardiomyocytes by posttreatment with vanadyl sulfate from MI/R injury was mediated by increased FLIP expression and decreased Fas ligand and Bim expression via activation of Akt. These results demonstrate that treatment with vanadyl sulfate exerts significant cardioprotective effects along with cardiac functional recovery.

Cardioprotection by Vanadium Compounds Targeting Akt-Mediated Signaling

“…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.…”

“…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).…”

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

“…3 However, drugs targeting activation of Akt have not been developed in the hypertrophy-induced cardiac remodeling. Thus, we hypothesize that stimulator of phosphatidylinositol 3-kinase/Akt signaling likely inhibits cardiac remodeling via upregulation of eNOS in the cardiomyocytes.We [17][18][19] and others 20 have shown that vanadium compounds are potent Akt activators with cytoprotective action …”

“…We [17][18][19] and others 20 have shown that vanadium compounds are potent Akt activators with cytoprotective action…”

“…We [17][18][19] and others 20 have shown that vanadium compounds are potent Akt activators with cytoprotective action against myocardial ischemia/reperfusion injury. In addition, we recently introduced a novel vanadyl (IV) compound having V O 2ϩ chelate, bis(1-oxy-2-pyridinethiolato) oxovanadium (IV), [VO[(OPT)], as potent activator of protein kinase B/Akt, thereby protecting cardiomyocytes from ischemia/ reperfusion injury in rats 18 and in mouse brain ischemia.…”