Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy.
Department of Experimental Medicine, University of Campania "L. Vanvitelli", 80138 Naples, Italy.
Int J Mol Sci. 2020 Oct 26;21(21):7927. doi: 10.3390/ijms21217927.
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-kit/Gata4 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.
3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶抑制剂（他汀类药物）对心脏细胞生物学具有多种作用，但尚未完全了解。在这里，我们测试了他汀类药物治疗是否会影响心肌梗死后体内和体外的内源性心脏干细胞/祖细胞（CSC）的激活。他汀类药物（瑞舒伐他汀、辛伐他汀和普伐他汀）通过 BrdU 掺入和细胞生长曲线显著增加了体外 CSC 的扩增。此外，他汀类药物增加了 CSC 的克隆扩增和心脏球体形成。他汀类药物对 CSC 生长和分化的影响取决于 Akt 磷酸化。通过永久性冠状动脉结扎在大鼠中诱导心肌梗死后 28 天，与未治疗对照组相比，瑞舒伐他汀治疗显著增加了梗塞边界区的内源性 CSC 数量。此外，激活的 CSC 向心肌谱系（c-kit/Gata4 CSC）的分化也增加了。因此，瑞舒伐他汀在心肌梗死后促进了新的心肌形成。最后，瑞舒伐他汀治疗逆转了 c-kit 杂合不足小鼠中 CSC 的心肌生成缺陷，增加了这些小鼠在心肌梗死后内源性 CSC 形成的新心肌细胞。总之，他汀类药物通过维持 Akt 激活，促进了体外和体内的 CSC 生长和分化。内源性 CSC 池的激活和分化以及他汀类药物随后形成的新心肌细胞，改善了啮齿动物冠状动脉闭塞后的心肌重构。类似的作用可能有助于他汀类药物对人类心血管疾病的有益作用。
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