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Acacetin ameliorates cardiac hypertrophy by activating Sirt1/AMPK/PGC-1α pathway
Yu-Kai Cui1, Yi-Xiang Hong1, Wei-Yin Wu1
1Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, 361009, China.
Abstract:
Cardiac hypertrophy is a major risk factor for developing heart failure. This study investigates the effects of the natural flavone acacetin on myocardial hypertrophy in cellular level and whole animals. In cardiomyocytes from neonatal rat with hypertrophy induced by angiotensin II (Ang II), acacetin at 0.3, 1, and 3 μM reduced the increased myocyte surface area, brain natriuretic peptide (BNP), and ROS production by upregulating anti-oxidative molecules (i.e. Nrf2, SOD1, SOD2, HO-1), anti-apoptotic protein Bcl-2, and downregulating the pro-apoptotic protein Bax and the inflammatory cytokine IL-6 in a concentration-dependent manner. In addition, acacetin rescued Ang II-induced impairment of PGC-1α, PPARα and pAMPK. These beneficial effects of acacetin were mediated by activation of Sirt1, which was confirmed in cardiac hypertrophy induced by abdominal aorta constriction (AAC) in SD rats. Acacetin prodrug (10 mg/kg, s.c., b.i.d.) treatment reduced the elevated artery blood pressure, improved the increased heart size and thickness of left ventricular wall and the ventricular fibrosis associated with inhibiting myocardial fibrosis and BNP, and reversed the impaired protective signal molecules including PGC-1α, Nrf2, PPARα, pAMPK and Sirt1 of left ventricular tissue. Our results demonstrate the novel pharmacological effect that acacetin ameliorates cardiac hypertrophy via Sirt1-mediated activation of AMPK/PGC-1α signal molecules followed by reducing oxidation, inflammation and apoptosis.
Insights
The natural flavone acacetin effectively reduces cardiac hypertrophy by activating Sirt1, which in turn boosts protective signaling pathways. This action combats oxidation, inflammation, and apoptosis, offering a potential therapeutic strategy for heart conditions.
Area of Science:
- Cardiovascular Biology
- Molecular Pharmacology
- Natural Product Chemistry
Background:
- Cardiac hypertrophy is a significant risk factor for heart failure.
- Identifying novel therapeutic agents for cardiac hypertrophy is crucial.
Purpose of the Study:
- To investigate the effects of the natural flavone acacetin on cardiac hypertrophy.
- To elucidate the molecular mechanisms underlying acacetin's action.
Main Methods:
- In vitro studies using neonatal rat cardiomyocytes treated with angiotensin II (Ang II).
- In vivo studies using spontaneously hypertensive rats (SD rats) with abdominal aorta constriction (AAC).
- Assessment of myocyte surface area, oxidative stress markers, apoptosis-related proteins, inflammatory cytokines, and key signaling pathways (Sirt1, AMPK, PGC-1α, Nrf2, PPARα).
Main Results:
- Acacetin reduced myocyte surface area, oxidative stress (ROS), and inflammation (IL-6) in vitro.
- Acacetin upregulated anti-oxidative (Nrf2, SOD1, SOD2, HO-1) and anti-apoptotic (Bcl-2) proteins while downregulating pro-apoptotic (Bax) proteins.
- In vivo, acacetin treatment lowered blood pressure, improved cardiac structure, reduced fibrosis, and reversed impaired signaling pathways, all mediated by Sirt1 activation.
Conclusions:
- Acacetin ameliorates cardiac hypertrophy through Sirt1-mediated activation of AMPK/PGC-1α signaling.
- This mechanism involves reducing oxidation, inflammation, and apoptosis in cardiac tissue.
- Acacetin demonstrates significant therapeutic potential for managing cardiac hypertrophy and preventing heart failure.
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