Abstract 1124: Statins Foster Cardiac Stem Cell Activation and New Myocyte Formation after Acute Neurohumoral Overload
Several studies have suggested that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) benefit patients with ischemic and nonischemic cardiomyopathy. Statins exert pleiotropic effects on cardiac biology which are not yet fully understood. The adult mammalian heart possesses a pool of c-kitpos cardiac stem cells (CSCs), which are activated in response to cardiac stress. Here we tested whether statin treatment affects CSC activation and resultant myocyte differentiation in an in vivo assay of myocardial-regeneration with patent coronary circulation. A single dose of isoproterenol (ISO; 5mgkg−1) was employed to induce diffuse myocyte damage in rats. This damage determines CSC activation and new myocyte formation. Saline was used in control rats (CTRL). ISO-treated rats were then administered simvastatin (SIM; 50mgkg−1) or placebo (PL). Animals were sacrificed 3, 7 and 14 days after ISO. New myocyte formation was tracked by BrdU administration. Myocyte apoptosis (hairpin 1), formation (BrdUpos/Ki67pos), CSC number and their myocyte-committed progeny (c-kitpos/ MEF2Cpos) were all evaluated by confocal microscopy. Myocyte hypertrophy was evident 3 days after ISO, but SIM administration blunted ISO-induced hypertrophy. Significantly, ISO-induced myocyte apoptosis was almost abolished by SIM. The number of c-kitpos CSCs increased more rapidly in SIM-treated rats compared to PL, from 3 through 14 days after ISO. Differentiation of the activated CSCs into the myogenic lineage (c-kitpos/MEF2Cpos) was increased in SIM as compared to PL, 3 to 14 days after ISO. Accordingly, the fraction of newly-formed myocytes (BrdUpos) in PL-treated rats reached 35% 28 days after ISO, but this amount was attained by day 14 in the SIM group. Importantly, most of the new myocytes showed a mature size by 28 days in SIM-treated rats. Additionally, SIM-treatment resulted in better LV function, compared to PL-treated animals. In conclusion, statins preserve myocardial structure and function after acute neurohumoral overload by a combination of processes: Protective effect on myocyte hypertrophy and death, together with a stimulation of new myocyte formation through activation and differentiation of the CSC pool.