Abstract
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−1 ·d−1, 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.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China [grant numbers 81374009, U1501222, and 81773720], Guangdong Natural Science Foundation [grant number 2016A030313570], Guangdong Medical Science and Technology Research Foundation [grant number A2018406], Guangzhou Science and Technology Project [grant number 201804010490], Guangzhou Education Bureau [grant number 2012C090], and Key Medical Disciplines and Specialties Program of Guangzhou [2017–2019].
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Participated in research design: NH, YH, SAC, WCY, CFL, and MSC. Conducted experiments: NH, YH, SAC, WCY, XWL, AQL, CFC, LRL, and GJZ. Supervised experiments: CFL and MSC. Performed data analysis: YH, NH, SAC, WCY, and LRL. Contributed new reagents or analytic tools: XXQ, DFC, JXX, SML, and XHC. Wrote or contributed to the writing of the manuscript: NH, YH, and CFL.
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Hou, N., Huang, Y., Cai, Sa. et al. Puerarin ameliorated pressure overload-induced cardiac hypertrophy in ovariectomized rats through activation of the PPARα/PGC-1 pathway. Acta Pharmacol Sin 42, 55–67 (2021). https://doi.org/10.1038/s41401-020-0401-y
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DOI: https://doi.org/10.1038/s41401-020-0401-y
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