4.5 Article

ICS II protects against cardiac hypertrophy by regulating metabolic remodelling, not by inhibiting autophagy

Journal

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 25, Issue 2, Pages 1074-1088

Publisher

WILEY
DOI: 10.1111/jcmm.16175

Keywords

autophagy; cardiac hypertrophy; Icariside II; ketone body; SIRT3

Funding

  1. Program for Talents in Scientific and Technological Innovation in Universities of Henan Province [19HASTIT002]
  2. National Natural Science Foundation of China [81873493]

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This study demonstrates that ICS II treatment can alleviate pressure overload-induced cardiac hypertrophy, protect heart function, reduce apoptosis and oxidative stress, as well as inhibit excessive autophagy in the heart and cardiomyocytes. Activation of the SIRT3-AMPK pathway plays a role in this protective effect.
Cardiac hypertrophy is characterized by a shift in metabolic substrate utilization. Therefore, the regulation of ketone body uptake and metabolism may have beneficial effects on heart injuries that induce cardiac remodelling. In this study, we investigated whether icariside II (ICS II) protects against cardiac hypertrophy in mice and cardiomyocytes. To create cardiac hypertrophy animal and cell models, mice were subjected to transverse aortic constriction (TAC), and embryonic rat cardiomyocytes (H9C2) were stimulated with angiotensin II, a neurohumoral stressor. Both the in vivo and in vitro results suggest that ICS II treatment ameliorated pressure overload-induced cardiac hypertrophy and preserved heart function. In addition, apoptosis and oxidative stress were reduced in the presence of ICS II. Moreover, ICS II inhibited excess autophagy in TAC-induced hearts and angiotensin II-stimulated cardiomyocytes. Mechanistically, we found that ICS II administration regulated SIRT3 expression in cardiac remodelling. SIRT3 activation increased ketone body transportation and utilization. Collectively, our data show that ICS II attenuated cardiac hypertrophy by modulating ketone body and fatty acid metabolism, and that this was likely due to the activation of the SIRT3-AMPK pathway. ICS II treatment may provide a new therapeutic strategy for improving myocardial metabolism in cardiac hypertrophy and heart failure.

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