NAD+ attenuates cardiac injury after myocardial infarction in diabetic mice through regulating alternative splicing of VEGF in macrophages

  • Vascul Pharmacol. 2022 Nov 6;147:107126. doi: 10.1016/j.vph.2022.107126.
Lei Jiao  1 ,  Manyu Gong  1 ,  Xuewen Yang  1 ,  Mengmeng Li  1 ,  Yingchun Shao  1 ,  Yaqi Wang  1 ,  Haodong Li  1 ,  Qi Yu  1 ,  Lihua Sun  1 ,  Lina Xuan  1 ,  Jian Huang  2 ,  Yanying Wang  1 ,  Dongping Liu  1 ,  Yunmeng Qu  1 ,  Xiuwen Lan  3 ,  Yanwei Zhang  1 ,  Xiyang Zhang  1 ,  Han Sun  1 ,  Yong Zhang  1 ,  Ying Zhang  4 ,  Baofeng Yang  5
Affiliations
  • 1. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China.
  • 2. The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin 150040, PR China.
  • 3. Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin 150040, PR China.
  • 4. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China. Electronic address: [email protected].
  • 5. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China; Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia; Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019RU070, PR China. Electronic address: [email protected].
PMID: 36351515 DOI: 10.1016/j.vph.2022.107126
Abstract

Diabetic mellitus (DM) complicated with myocardial infarction (MI) is a serious clinical issue that remained poorly comprehended. The aim of the present study was to investigate the role of NAD+ in attenuating cardiac damage following MI in diabetic mice. The cardiac dysfunction in DM mice with MI was more severe compared with the non-diabetic mice and NAD+ administration could significantly improve the cardiac function in both non-diabetic and diabetic mice after MI for both 7 days and 28 days. Moreover, application of NAD+ could markedly reduce the cardiac injury area of DM complicated MI mice. Notably, the level of NAD+ was robustly decreased in the cardiac tissue of MI mice, which was further reduced in the DM complicated mice and NAD+ administration could significantly restore the NAD+ level. Furthermore, NAD+ was verified to facilitate the angiogenesis in the MI area of both diabetic mice and non-diabetic mice by microfil perfusion assay and immunofluorescence. Additionally, we demonstrated that NAD+ promoted cardiac angiogenesis after myocardial infarction in diabetic mice by promoting the M2 polarization of macrophages. At the molecular level, NAD+ promoted the secretion of VEGF in macrophages and therefore facilitating migration and tube formation of endothelial cells. Mechanistically, NAD+ was found to promote the generation of pro-angionesis VEGF165 and inhibit the generation of anti-angionesis VEGF165b via regulating the alternative splicing factors of VEGF (SRSF1 and SRSF6) in macrophages. The effects of NAD+ were readily reversible on deficiency of it. Collectively, our data showed that NAD+ could attenuate myocardial injury via regulating the alternative splicing of VEGF and promoting angiogenesis in diabetic mice after myocardial infarction. NAD+ administration may therefore be considered a potential new approach for the treatment of diabetic patients with myocardial infarction.

Keywords
Alternative splicing; Diabetic mellitus; Myocardial infarction; NAD(+); VEGF.
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