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ALDH2 protects against high fat diet-induced obesity cardiomyopathy and defective autophagy: role of CaM kinase II, histone H3K9 methyltransferase SUV39H, Sirt1, and PGC-1α deacetylation

International Journal of Obesity volume 42, pages 1073–1087 (2018)Cite this article

Subjects

A Correction to this article was published on 27 November 2019

This article has been updated

Abstract

Background and aims

Uncorrected obesity contributes to cardiac remodeling and contractile dysfunction although the underlying mechanism remains poorly understood. Mitochondrial aldehyde dehydrogenase (ALDH2) is a mitochondrial enzyme with some promises in a number of cardiovascular diseases. This study was designed to evaluate the impact of ALDH2 on cardiac remodeling and contractile property in high fat diet-induced obesity.

Methods

Wild-type (WT) and ALDH2 transgenic mice were fed low (10% calorie from fat) or high (45% calorie from fat) fat diet for 5 months prior to the assessment of cardiac geometry and function using echocardiography, IonOptix system, Lectin, and Masson Trichrome staining. Western blot analysis was employed to evaluate autophagy, CaM kinase II, PGC-1α, histone H3K9 methyltransferase SUV39H, and Sirt-1.

Results

Our data revealed that high fat diet intake promoted weight gain, cardiac remodeling (hypertrophy and interstitial fibrosis, p < 0.0001) and contractile dysfunction (reduced fractional shortening (p < 0.0001), cardiomyocyte function (p < 0.0001), and intracellular Ca2+ handling (p = 0.0346)), mitochondrial injury (elevated O2− levels, suppressed PGC-1α, and enhanced PGC-1α acetylation, p < 0.0001), elevated SUV39H, suppressed Sirt1, autophagy and phosphorylation of AMPK and CaM kinase II, the effects of which were negated by ALDH2 (p ≤ 0.0162). In vitro incubation of the ALDH2 activator Alda-1 rescued against palmitic acid-induced changes in cardiomyocyte function, the effect of which was nullified by the Sirt-1 inhibitor nicotinamide and the CaM kinase II inhibitor KN-93 (p < 0.0001). The SUV39H inhibitor chaetocin mimicked Alda-1-induced protection again palmitic acid (p < 0.0001). Examination in overweight human revealed an inverse correlation between diastolic cardiac function and ALDH2 gene mutation (p < 0.05).

Conclusions

Taken together, these data suggest that ALDH2 serves as an indispensable factor against cardiac anomalies in diet-induced obesity through a mechanism related to autophagy regulation and facilitation of the SUV39H-Sirt1-dependent PGC-1α deacetylation.

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  • 27 November 2019

    The authors found a critical mistake in the assembly of Fig. 2; in Fig. 2A the right two images were erroneously duplicated. The authors have re-analysed all the data, checked for accuracy and provided the updated Fig. 2 here. Nothing is affected with regards to data summary and conclusion.

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Acknowledgements

SW was supported by the University of Wyoming Biomedical Science PhD program.

Funding

American Diabetes Association (7-13-BS-142-BR), NSFC 81370195, NSFC81570225, NSFC81521001, and NSFC 81522004.

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Author notes

  1. These authors contributed equally: Shuyi Wang and Cong Wang.

Authors and Affiliations

  1. Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032, Shanghai, China

    Shuyi Wang, Cong Wang, Yingmei Zhang & Jun Ren

  2. Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA

    Shuyi Wang, Subat Turdi, Kacy L. Richmond, Yingmei Zhang & Jun Ren

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  1. Shuyi Wang
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  2. Cong Wang
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SW, CW, ST, KLR, YZ, data collection; YZ and JR: study design, funding, and manuscript writing.

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Correspondence to Yingmei Zhang or Jun Ren.

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Wang, S., Wang, C., Turdi, S. et al. ALDH2 protects against high fat diet-induced obesity cardiomyopathy and defective autophagy: role of CaM kinase II, histone H3K9 methyltransferase SUV39H, Sirt1, and PGC-1α deacetylation. Int J Obes 42, 1073–1087 (2018). https://doi.org/10.1038/s41366-018-0030-4

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