Prevention of Cardiac Hypertrophy by Atorvastatin in a Transgenic Rabbit Model of Human Hypertrophic Cardiomyopathy

Abstract

Abstract-Cardiac hypertrophy, a major determinant of morbidity and mortality in hypertrophic cardiomyopathy (HCM), is considered a secondary phenotype and potentially preventable. To test this hypothesis, we screened 30 5-to 6-month-old ␤-myosin heavy chain Q403 transgenic rabbits by echocardiography and selected 26 without cardiac hypertrophy. We randomized the transgenic rabbits to treatment with atorvastatin (2.5 mg/Kg/d), known to block hypertrophic signaling or a placebo. We included 15 nontransgenic rabbits as controls. Cardiac phenotype was analyzed serially before, 6 and 12 months after randomization. Serum total cholesterol levels were reduced by 49% with atorvastatin administration. Left-ventricular mass, wall thickness; myocyte size, myocardial levels of molecular markers of hypertrophy, lipid peroxides, and oxidized mitochondrial DNA; and the number of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive myocytes were increased significantly in the placebo but not in the atorvastatin group. Myocardium catalase mRNA levels were decreased by 5-fold in the placebo but were normal in the atorvastatin group. Catalase protein level and activity were not significantly changed. Levels of membrane-bound Ras and phospho-p44/42 mitogen-activated-protein kinase (MAPK) were increased in the placebo group (Ϸ2.5 fold) but were reduced in the atorvastatin group. Levels of GTP-and membrane-bound RhoA and Rac1, phospho-p38, and phospho-c-Jun NH2-terminal kinases were unchanged. Thus, atorvastatin prevented development of cardiac hypertrophy; determined at organ, cellular, and molecular levels, partly through reducing active Ras and p44/42 MAPK. The results indicate potential beneficial effects of atorvastatin in prevention of cardiac hypertrophy, a major determinant of morbidity in all forms of cardiovascular diseases, and beckon clinical studies in humans with HCM.

Simvastatin inhibited cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice fed a “Western-style diet” by increasing PPAR α and γ expression and reducing TC, MMP-9, and Cat S levels

“…Treatment with simvastatin prevented the cardiac hypertrophy and fibrosis with a significant increase in the mRNA and protein levels of PPAR alpha and PPAR gamma at 32 weeks and 40 weeks. The results are in accordance with the effects of statins for the prevention of cardiac hypertrophy by activating the PPAR pathway and reducing the generation of reactive oxygen species [8,9] . PPAR alpha, the predominant PPAR isoform in the heart, has been implicated in hypertrophic signaling.…”

“…The observed beneficial effects of simvastatin in the ApoE-/-mice fed a "Western-style diet" are in accordance with the effects of statins in the prevention of norepinephrine-induced myocyte hypertrophy [27] , a transgenic rabbit model of human hypertrophic cardiomyopathy [8] and pressure overloadinduced hypertrophy in rats [7] . One study provided evidence that rosuvastatin ameliorated cardiac hypertrophy and fibrosis during hypercholesterolemia in low-density lipoprotein receptor knockout mice fed a high cholesterol diet [26] .…”

“…Ten areas were taken at random from each of 4 separate heart samples per group (40 images per group). Morphometric analysis [8] of 10 randomly selected fields per section from 10 sections per mouse was performed by an investigator who was blinded to the treatment protocol.…”

“…Statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have been reported to reverse established cardiac hypertrophy and interstitial fibrosis. This effect may be mediated by reducing the generation of reactive oxygen species and through the peroxisome proliferator activated receptor (PPAR) pathway [5][6][7][8] . PPAR alpha, the predominant PPAR isoform in the heart, has been implicated in hypertrophic signaling.…”

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

“…These inhibitors of the posttranscriptional lipid modifications of RAS are likely to be effective, because they have been shown to exert antitumoral action in different cancer cells with mutations on RAS (125,126). Indeed, statins reduced cardiac hypertrophy in a transgenic model of HCM (127,128). A combination of low doses of statins and specific inhibitors of pathological ERK1/2 signaling represents, at the moment, a pretty exciting possibility still to be explored.…”