Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China.
Key Laboratory of Molecular Target and Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
Acta Pharmacol Sin. 2021 Jan;42(1):55-67. doi: 10.1038/s41401-020-0401-y. Epub 2020 Jun 5.
Estrogen deficiency induces cardiac dysfunction and increases the risk of cardiovascular disease in postmenopausal women and in those who underwent bilateral oophorectomy. Previous evidence suggests that puerarin, a phytoestrogen, exerts beneficial effects on cardiac function in patients with cardiac hypertrophy. In this study, we investigated whether puerarin could prevent cardiac hypertrophy and remodeling in ovariectomized, aortic-banded rats. Female SD rats subjected to bilateral ovariectomy (OVX) plus abdominal aortic constriction (AAC). The rats were treated with puerarin (50 mg·kg ·d, ip) for 8 weeks. Then echocardiography was assessed, and the rats were sacrificed, their heart tissues were extracted and allocated for further experiments. We showed that puerarin administration significantly attenuated cardiac hypertrophy and remodeling in AAC-treated OVX rats, which could be attributed to activation of PPARα/PPARγ coactivator-1 (PGC-1) pathway. Puerarin administration significantly increased the expression of estrogen-related receptor α, nuclear respiratory factor 1, and mitochondrial transcription factor A in hearts. Moreover, puerarin administration regulated the expression of metabolic genes in AAC-treated OVX rats. Hypertrophic changes could be induced in neonatal rat cardiomyocytes (NRCM) in vitro by treatment with angiotensin II (Ang II, 1 μM), which was attenuated by co-treatemnt with puerarin (100 μM). We further showed that puerarin decreased Ang II-induced accumulation of non-esterified fatty acids (NEFAs) and deletion of ATP, attenuated the Ang II-induced dissipation of the mitochondrial membrane potential, and improved the mitochondrial dysfunction in NRCM. Furthermore, addition of PPARα antagonist GW6471 (10 μM) partially abolished the anti-hypertrophic effects and metabolic effects of puerarin in NRCM. In conclusion, puerarin prevents cardiac hypertrophy in AAC-treated OVX rats through activation of PPARα/PGC-1 pathway and regulation of energy metabolism remodeling. This may provide a new approach to prevent the development of heart failure in postmenopausal women.
雌激素缺乏会导致绝经后妇女和双侧卵巢切除术后妇女的心脏功能障碍，并增加心血管疾病的风险。先前的证据表明，葛根素作为一种植物雌激素，对心脏肥厚患者的心脏功能有有益的影响。在这项研究中，我们研究了葛根素是否可以预防去卵巢加腹主动脉缩窄（AAC）大鼠的心脏肥大和重塑。雌性 SD 大鼠接受双侧卵巢切除术（OVX）加腹主动脉缩窄（AAC）。大鼠用葛根素（50mg·kg·d，ip）治疗 8 周。然后进行超声心动图评估，处死大鼠，提取心脏组织并分配用于进一步实验。我们表明，葛根素给药显著减轻 AAC 处理的 OVX 大鼠的心脏肥大和重塑，这可能归因于过氧化物酶体增殖物激活受体α/过氧化物酶体增殖物激活受体γ共激活因子-1（PGC-1）通路的激活。葛根素给药显著增加了心脏中雌激素相关受体α、核呼吸因子 1 和线粒体转录因子 A 的表达。此外，葛根素给药调节 AAC 处理的 OVX 大鼠代谢基因的表达。在体外，用血管紧张素 II（Ang II，1μM）处理新生大鼠心肌细胞（NRCM）可诱导肥大变化，并用葛根素（100μM）共同处理可减轻。我们进一步表明，葛根素可减少 Ang II 诱导的非酯化脂肪酸（NEFAs）积累和 ATP 缺失，减轻 Ang II 诱导的线粒体膜电位耗散，并改善 NRCM 的线粒体功能障碍。此外，添加 PPARα 拮抗剂 GW6471（10μM）部分消除了葛根素在 NRCM 中的抗肥大作用和代谢作用。总之，葛根素通过激活 PPARα/PGC-1 通路和调节能量代谢重塑来预防 AAC 处理的 OVX 大鼠的心脏肥大。这可能为预防绝经后妇女心力衰竭的发展提供一种新方法。
