Development of heart failure with preserved ejection fraction in type 2 diabetic mice is ameliorated by preserving vascular function

Life Sci. 2021 Nov 1:284:119925. doi: 10.1016/j.lfs.2021.119925. Epub 2021 Sep 1.


Aims: Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction and is frequent in people with type 2 diabetes mellitus. In diabetic patients, increased levels of the eicosanoid 12-hydroxyeicosatetraenoic acid (12-HETE) are linked to vascular dysfunction. Here, we aimed to identify the importance of 12-HETE in type 2 diabetic patients exhibiting diastolic dysfunction, and mice exhibiting HFpEF and whether targeting 12-HETE is a means to ameliorate HFpEF progression by improving vascular function in diabetes.

Material and methods: Subjects with diagnosed type 2 diabetes mellitus and reported diastolic dysfunction or healthy controls were recruited and 12(S)-HETE levels determined by ELISA. 12(S)-HETE levels were determined in type 2 diabetic, leptin receptor deficient mice (LepRdb/db) and HFpEF verified by echocardiography. Mitochondrial function, endothelial function and capillary density were assessed using Seahorse technique, pressure myography and immunohistochemistry in LepRdb/db or non-diabetic littermate controls. 12/15Lo generation was inhibited using ML351 and 12(S)-HETE action by using the V1-cal peptide.

Key findings: Endothelium-dependent vasodilation and mitochondrial functional capacity both improved in response to either application of ML351 or the V1-cal peptide. Correlating to improved vascular function, mice treated with either pharmacological agent exhibited improved diastolic filling and left ventricular relaxation that correlated with increased myocardial capillary density.

Significance: Our results suggest that 12-HETE may serve as a biomarker indicating endothelial dysfunction and the resulting cardiovascular consequences such as HFpEF in type 2 diabetic patients. Antagonizing 12-HETE is a potent means to causally control HFpEF development and progression in type 2 diabetes by preserving vascular function.

Keywords: Diabetes; Eicosanoids; Endothelial dysfunction; HFpEF; Heart failure; Mitochondria.

MeSH terms

  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / metabolism
  • Aged
  • Animals
  • Blood Vessels / physiopathology*
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / physiopathology*
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Diastole
  • Endothelial Cells / metabolism
  • Female
  • Heart Failure / physiopathology*
  • Heart Ventricles / physiopathology
  • Humans
  • Male
  • Mice
  • Mitochondria / metabolism
  • Stroke Volume / physiology*
  • TRPV Cation Channels / metabolism
  • Vasodilation


  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid