title: 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 (p40(phox) and gp91(phox) subunits) and nuclear factor-kappaB (NF-kappaB). Rosuvastatin attenuated the Ang II-mediated upregulation of both subunits of NAPDH oxidase as well as NF-kappaB. 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.
authors.affiliation: Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Bum-Yong
authors.initials: BY
authors.lastname: Kang
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D018929:Cell Culture Techniques; D048429:Cell Size / Q000187:drug effects; D005464:Fluorobenzenes / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D051127:Scavenger Receptors, Class E / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D052002:NF-kappa B p50 Subunit; C495138:Olr1 protein, mouse; D011743:Pyrimidines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D051127:Scavenger Receptors, Class E; D013449:Sulfonamides; D000804:Angiotensin II; C073701:Nfkb1 protein, mouse; D009249:NADP; D000068718:Rosuvastatin Calcium; D019808:Losartan