Rosuvastatin Attenuates Ang II—Mediated Cardiomyocyte Hypertrophy via Inhibition of LOX-1

Abstract

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, also known as statins, have been shown to reduce cardiac remodeling. Angiotensin II (Ang II) type 1 receptor (AT1R) and oxidized low-density lipoprotein (ox-LDL) via its lectin-like ox-LDL receptor (LOX-1) are major stimuli for cardiomyocyte growth. We postulated that rosuvastatin, a potent HMG-CoA reductase inhibitor, may reduce Ang II—mediated cardiomyocyte growth via AT1R and LOX-1 inhibition. HL-1 adult mouse cardiomyocytes were incubated overnight in serum-free medium, and then treated with rosuvastatin, the AT1R inhibitor losartan or anti-LOX-1 antibody for 3 hours. The cells were then stimulated with Ang II. We measured cardiomyocyte growth, and associated intracellular redox signals using reverse transcription— polymerase chain reaction (RT-PCR) and real-time quantitative PCR. Losartan and anti-LOX-1 antibody markedly attenuated Ang II—mediated oxidant stress, and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p40pho x and gp91 phox subunits) and nuclear factor-κB (NF-κB). Rosuvastatin attenuated the Ang II—mediated upregulation of both subunits of NAPDH oxidase as well as NF-κB. Rosuvastatin also reduced Ang II—mediated upregulation of AT1R and LOX-1. In other experiments, LOX-1 was upregulated in cardiomyocytes by transfection with pCI-neo/LOX-1, which also enhanced the expression AT1R messenger RNA (mRNA), and rosuvastatin pretreatment reduced the expression of both LOX-1 and AT1R in this system. Thus, rosuvastatin attenuates Ang II—mediated cardiomyocyte growth by inhibiting LOX-1 and AT1R expression and suppressing the heightened intracellular redox state.