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

Vascul Pharmacol. 2022 Dec:147:107126. doi: 10.1016/j.vph.2022.107126. Epub 2022 Nov 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Diabetes Mellitus*
  • Endothelial Cells
  • Macrophages
  • Mice
  • Myocardial Infarction*
  • NAD / pharmacology
  • NAD / therapeutic use
  • Neovascularization, Pathologic
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • NAD
  • Vascular Endothelial Growth Factor A