2. Academic Validation
  3. A Novel ALDH2 Activator AD-9308 Improves Diastolic and Systolic Myocardial Functions in Streptozotocin-Induced Diabetic Mice

A Novel ALDH2 Activator AD-9308 Improves Diastolic and Systolic Myocardial Functions in Streptozotocin-Induced Diabetic Mice

  • Antioxidants (Basel). 2021 Mar 13;10(3):450. doi: 10.3390/antiox10030450.
Hsiao-Lin Lee 1,  Siow-Wey Hee 1,  Chin-Feng Hsuan 2 3 4,  Wenjin Yang 5,  Jing-Yong Huang 1,  Ya-Ling Lin 1,  Chih-Neng Hsu 6,  Juey-Jen Hwang 1 6,  Shiau-Mei Chen 1,  Zhi-Zhong Ding 7,  Tung-Yuan Lee 7,  Yu-Chiao Lin 8,  Feng-Chiao Tsai 1 8,  Wei-Lun Su 1,  Li-Yun Chueh 8,  Meng-Lun Hsieh 1 8,  Che-Hong Chen 9,  Daria Mochly-Rosen 9,  Yi-Cheng Chang 1 7 10,  Lee-Ming Chuang 1 11 12
Affiliations

Affiliations

  • 1 Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan.
  • 2 Division of Cardiology, Department of Internal Medicine, E-Da Hospital, Kaohsiung 824410, Taiwan.
  • 3 Division of Cardiology, Department of Internal Medicine, E-Da Dachang Hospital, Kaohsiung 82445, Taiwan.
  • 4 School of Medicine, College of Medicine, I-Shou University, Kaohsiung 840203, Taiwan.
  • 5 Foresee Pharmaceuticals, Co., Ltd., Taipei 11560, Taiwan.
  • 6 Department of Internal Medicine, National Taiwan University Hospital, Yunlin Branch, Yunlin 64041, Taiwan.
  • 7 Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei 10055, Taiwan.
  • 8 Department of Pharmacology, National Taiwan University, Taipei 100233, Taiwan.
  • 9 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 10 Institute of Biomedical Sciences, Academia Sinica, Taipei 115024, Taiwan.
  • 11 Graduate Institute of Molecular Medicine, National Taiwan University, Taipei 100233, Taiwan.
  • 12 Graduate Institute of Clinical Medicine, National Taiwan University, Taipei 100233, Taiwan.
PMID: 33805825 DOI: 10.3390/antiox10030450
Abstract

Diabetes mellitus has reached epidemic proportion worldwide. One of the diabetic complications is cardiomyopathy, characterized by early left ventricular (LV) diastolic dysfunction, followed by development of systolic dysfunction and ventricular dilation at a late stage. The pathogenesis is multifactorial, and there is no effective treatment yet. In recent years, 4-hydroxy-2-nonenal (4-HNE), a toxic aldehyde generated from lipid peroxidation, is implicated in the pathogenesis of cardiovascular diseases. Its high bioreactivity toward proteins results in cellular damage. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that detoxifies 4-HNE. The development of small-molecule ALDH2 activator provides an opportunity for treating diabetic cardiomyopathy. This study found that AD-9308, a water-soluble andhighly selective ALDH2 activator, can improve LV diastolic and systolic functions, and wall remodeling in streptozotocin-induced diabetic mice. AD-9308 treatment dose-dependently lowered serum 4-HNE levels and 4-HNE protein adducts in cardiac tissue from diabetic mice, accompanied with ameliorated myocardial fibrosis, inflammation, and Apoptosis. Improvements of mitochondrial functions, sarco/endoplasmic reticulumcalcium handling and Autophagy regulation were also observed in diabetic mice with AD-9308 treatment. In conclusion, ADLH2 activation effectively ameliorated diabetic cardiomyopathy, which may be mediated through detoxification of 4-HNE. Our findings highlighted the therapeutic potential of ALDH2 activation for treating diabetic cardiomyopathy.

Keywords

4-hydroxy-2-nonenal; AD-9308; diabetic cardiomyopathy; mitochondrial aldehyde dehydrogenase 2.

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