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Published on: July 14, 2016
Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy
Lei Wang1, Xue-Qing Tang1, Yang Shi1
1Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
Insights
Tetrahydroberberrubine (THBru) and berberine (BBR) show protective effects against heart aging by mitigating cardiac dysfunction and promoting mitophagy. THBru is a potent antiaging compound, inducing prohibitin 2 (PHB2)-mediated mitophagy for potential clinical application.
Area of Science:
- Cardiovascular Science
- Gerontology
- Pharmacology
Background:
- Heart aging is associated with left ventricular hypertrophy and diastolic dysfunction, leading to cardiovascular diseases.
- Current therapeutic options for age-related cardiac abnormalities are limited.
- Berberine (BBR) and its derivative tetrahydroberberrubine (THBru) were investigated for their potential anti-aging effects on the heart.
Purpose of the Study:
- To investigate the protective effects of BBR and THBru against D-galactose-induced heart aging in mice.
- To explore the underlying mechanisms, including mitophagy and prohibitin 2 (PHB2) expression, of THBru's anti-aging effects.
Main Methods:
- Heart aging was induced in mice using D-galactose injections over 12 weeks.
- Mice were treated with BBR or THBru orally for 12 weeks.
- Primary neonatal mouse cardiomyocytes were treated with D-galactose, BBR, or THBru in vitro to assess cellular senescence and mitophagy.
- PHB2 knockdown and overexpression were used to confirm its role in THBru's effects.
Main Results:
- BBR and THBru treatment significantly alleviated diastolic dysfunction and cardiac remodeling in aging mice.
- Both compounds inhibited D-galactose-induced senescence in cardiomyocytes; THBru showed higher efficacy.
- THBru and BBR promoted mitophagy, a process found to be decreased in aging hearts.
- THBru's mitophagy-inducing effect was linked to increased mRNA stability and protein expression of PHB2.
- PHB2 manipulation confirmed its critical role in mediating THBru's anti-senescence and mitophagy-promoting effects.
Conclusions:
- THBru demonstrates potent anti-aging effects on the heart, superior to BBR at equivalent doses.
- THBru acts by upregulating PHB2, thereby promoting mitophagy and reducing cardiomyocyte senescence.
- THBru holds promise as a novel therapeutic agent for age-related cardiac dysfunction and warrants further clinical investigation.
Abstract:
Heart aging is characterized by left ventricular hypertrophy and diastolic dysfunction, which in turn induces a variety of cardiovascular diseases. There is still no therapeutic drug to ameliorate cardiac abnormities in heart aging. In this study we investigated the protective effects of berberine (BBR) and its derivative tetrahydroberberrubine (THBru) against heart aging process. Heart aging was induced in mice by injection of D-galactose (D-gal, 120 mg · kg-1 · d-1, sc.) for 12 weeks. Meanwhile the mice were orally treated with berberine (50 mg · kg-1 · d-1) or THBru (25, 50 mg · kg-1 · d-1) for 12 weeks. We showed that BBR and THBru treatment significantly mitigated diastolic dysfunction and cardiac remodeling in D-gal-induced aging mice. Furthermore, treatment with BBR (40 μM) and THBru (20, 40 μM) inhibited D-gal-induced senescence in primary neonatal mouse cardiomyocytes in vitro. Overall, THBru exhibited higher efficacy than BBR at the same dose. We found that the levels of mitophagy were significantly decreased during the aging process in vivo and in vitro, THBru and BBR promoted mitophagy with different potencies. We demonstrated that the mitophagy-inducing effects of THBru resulted from increased mRNA stability of prohibitin 2 (PHB2), a pivotal factor during mitophagy, thereby upregulating PHB2 protein expression. Knockdown of PHB2 effectively reversed the antisenescence effects of THBru in D-gal-treated cardiomyocytes. On the contrary, overexpression of PHB2 promoted mitophagy and retarded cardiomyocyte senescence, as THBru did. In conclusion, this study identifies THBru as a potent antiaging medicine that induces PHB2-mediated mitophagy and suggests its clinical application prospects.
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