Abstract P077: Atorvastatin Ameliorates Cardiac Injury and Inflammation via Adiponectin-independent Activation of AMP-activated Protein Kinase and Inhibition of the Nf-κB Pathway in Rats With Metabolic Syndrome

Abstract

Background: Statins have been implicated in inhibition of inflammation and preventing new onset type 2 diabetes. However, the mechanism underlying the pleiotropic effects of statins remains controversial. We investigated the effects of atorvastatin on cardiac and adipose tissue pathology as well as glucose and lipid metabolism in rats with metabolic syndrome (MetS). Methods and Results: We used DahlS.Z-Leprfa/Leprfa (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of MetS. DS/obese rats were treated with atorvastatin (6 or 20 mg/kg/day, p.o.) from 9 to 13 weeks of age. Treatment with atorvastatin ameliorated LV fibrosis and diastolic dysfunction as well as LV oxidative stress and inflammation without affecting hypertension or LV hypertrophy in DS/obese rats. Atorvastatin did not affect visceral or subcutaneous fat mass but alleviated adipocyte hypertrophy (high-dose) and inflammation (both high- and low-dose) in visceral adipose tissue in these rats. Both high- and low-dose atorvastatin reduced serum adiponectin concentration in DS/obese rats. However, both doses of atorvastatin similarly attenuated the decrease in phosphorylation of AMP-activated protein kinase (AMPK) as well as the increase in phosphorylation of NF-kB in the heart. Insulin resistance was similarly improved by both high- and low-dose atorvastatin. Glucose intolerance was partially ameliorated by low-dose atorvastatin and completely prevented by high-dose atorvastatin. Both doses of atorvastatin similarly attenuated the increases in serum levels of total cholesterol, LDL-cholesterol, and triglycerides in DS/obese rats. Conclusions: Treatment of DS/obese rats with atorvastatin attenuated adipose tissue inflammation, without affecting obesity, as well as ameliorated LV inflammation, fibrosis and diastolic dysfunction and abnormal metabolism. The beneficial cardiac effects of atorvastatin are likely attributable, at least in part, to adiponectin-independent activation of AMPK and subsequent inhibition of the NF-κB pathway.