Abstract 1423: Pitavastatin Ameliorates Angiotensin II-induced Cardiorenal Insufficiency In eNOS Knockout Mice Through Attenuating Rac-1-mediated Oxidative Stress
Background: It is well known that angiotensin II (Ang II) generates reactive oxygen species through NADPH oxidase activation, leading to promotion of cardiorenal diseases, especially in a condition with decreased nitric oxide (NO) bioavailability. In previous scientific sessions, we have shown that pitavastatin, an HMGCoA reductase inhibitor, ameliorates Ang II-induced cardiorenal damage in eNOS knockout (KO) mice through inhibition of the TGF-β-Smad2/3 pathway. However, the mechanism underlying eNOS-independent protective actions by pitavastatin has not been fully elucidated.
Methods and Results: eNOS KO mice at 10 weeks of age were infused with Ang II (2.0 mg/kg/day) by an osmotic mini-pump for 2 weeks and they were divided into 3 treatment groups: pitavastatin (0.2 mg/kg/day), tempol, a free radical scavenger, (1.5 mg/kg/day), or a vehicle. Pitavastatin as well as tempol ameliorated Ang II-induced left ventricular hypertrophy with interstitial and pericoronary artery fibrosis and ameliorated diastolic dysfunction and they attenuated Ang II-induced glomerular damage, such as low glomerular filtration rate, increased albuminuria and PAS-positive glomerular depositions compared to those in vehicle-treated mice. Ang II-induced high mortality rate in eNOS KO mice was restored by pitavastatin as well as tempol treatment. Moreover, in eNOSKO mice, Ang II-induced cardiorenal superoxide production, detected with dihydroethidium staining, and Ang II-induced activity of rac-1-GTPase, a small G-protein involved in the activation of NADPH oxidase, were attenuated by pitavastatin treatment.
Conclusions: Pitavastatin exerts an eNOS-independent protective action against Ang II-induced cardiorenal insufficiency through attenuating rac-1-GTPase-mediated oxidative stress. Our findings suggest that pitavastatin treatment is useful for caridorenal protection in patients with impaired NO bioavailability.