Abstract
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert pleiotropic effects on cardiac cell biology which are not yet fully understood. Here we tested whether statin treatment affects resident endogenous cardiac stem/progenitor cell (CSC) activation in vitro and in vivo after myocardial infarction (MI). Statins (Rosuvastatin, Simvastatin and Pravastatin) significantly increased CSC expansion in vitro as measured by both BrdU incorporation and cell growth curve. Additionally, statins increased CSC clonal expansion and cardiosphere formation. The effects of statins on CSC growth and differentiation depended on Akt phosphorylation. Twenty-eight days after myocardial infarction by permanent coronary ligation in rats, the number of endogenous CSCs in the infarct border zone was significantly increased by Rosuvastatin-treatment as compared to untreated controls. Additionally, commitment of the activated CSCs into the myogenic lineage (c-kitpos/Gata4pos CSCs) was increased by Rosuvastatin administration. Accordingly, Rosuvastatin fostered new cardiomyocyte formation after MI. Finally, Rosuvastatin treatment reversed the cardiomyogenic defects of CSCs in c-kit haploinsufficient mice, increasing new cardiomyocyte formation by endogenous CSCs in these mice after myocardial infarction. In summary, statins, by sustaining Akt activation, foster CSC growth and differentiation in vitro and in vivo. The activation and differentiation of the endogenous CSC pool and consequent new myocyte formation by statins improve myocardial remodeling after coronary occlusion in rodents. Similar effects might contribute to the beneficial effects of statins on human cardiovascular diseases.
Highlights
The demonstration that new cardiomyocytes (CMs) are produced in the adult mammalian myocardium, albeit in limited amounts, generated a flurry of interest in harnessing this adult neo-cardiomyogensis to foster adult myocardial regeneration and repair in order to ameliorate the devastating impact of myocardial damage and heart failure in an aging human population [1,2,3]
Aside from the ongoing controversy, several studies have shown that cardiac stem/progenitor cell (CSC), apart from their cardiomyocyte regenerative potential, are promising regenerative agents for their paracrine action when used as allogenic cell therapy [10,11,12,13,14,15,16,17] and their regenerative potential can be fostered by several experimental approaches [3,10,11,12,13,18,19,20,21]
To assess the effects of statins on the rat CSC cell cycle activation in vitro, primary cultured CSCs at P1 were serum starved for 48 h and parallel cultures were treated either with 1 μM simvastatin (SIM), as a prototypical lipophilic hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, 1 μM rosuvastatin (ROSU) or 5 μM pravastatin (PRAVA), respectively, as new and old generation hydrophilic HMG-CoA reductase inhibitors, or just vehicle
Summary
The demonstration that new cardiomyocytes (CMs) are produced in the adult mammalian myocardium, albeit in limited amounts, generated a flurry of interest in harnessing this adult neo-cardiomyogensis to foster adult myocardial regeneration and repair in order to ameliorate the devastating impact of myocardial damage and heart failure in an aging human population [1,2,3] This paradigmatic change, together with the identification and characterization of adult cardiac stem cells (CSCs) [1] gave birth to the bourgeoning field of adult myocardial regeneration. While the discovery and characterization of the phenotype and regenerative potential of adult resident cardiac stem/progenitor cells was initially met as a significant advancement in cardiac biology, some recent data from genetic fate mapping studies have questioned the endogenous regenerative role of CSCs after myocardial infarction [4,5,6,7,8,9]. To gain further insights into the mechanisms by which statins improve myocardial remodeling, here we investigated the effects of statins on resident CSCs in vitro and in vivo
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