Cellular and Molecular Mechanisms of Endothelial Dysfunction in Diabetic Cardiomyopathy

Type 2 diabetes (T2D) is associated with cardiac microvascular dysfunction, which is thought to contribute to the development of diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF). The molecular mechanisms responsible for HFpEF remain unclear, and no effective diagnostics or main-stay treatments are available. To gain insight into biomarkers and disease mechanisms we measured the microRNA content of circulating extracellular vesicles (EVs) during pathogenesis in two animal models of T2D-associated HFpEF (i.e., obese mouse [Lepr-/-] and lean rat [Goto Kakizaki]). We found that miR-30d and miR-30e were increased prior to echocardiographic evidence of diastolic dysfunction in T2D mice, and they were also elevated in T2D rats with established diastolic dysfunction. These microRNAs may serve as biomarkers of cardiac microvascular dysfunction as they are upregulated in the endothelial cells (ECs) of the left ventricle of the heart, but not other organs. Furthermore, the miR-30 family is secreted in response to activation of senescence pathways, a characteristic feature of diabetic ECs. Assessment of pathways regulated by miR-30d/e revealed a large number of target genes involved in fatty acid biosynthesis and metabolism. Importantly, over-expression of miR-30e in ECs increased fatty acid oxidation and the production of reactive oxygen species, while inhibiting the miR-30 family decreased fatty acid oxidation. Additionally, miR-30e over-expression synergized with fatty acid exposure to dramatically down-regulate the expression of eNOS, an important regulator of microvascular and cardiomyocyte function. Thus, miR-30d/e may represent early biomarkers of diastolic dysfunction that reflect altered fatty acid metabolism and microvascular dysfunction in the heart. Furthermore, the pathways regulated by miR-30 may represent therapeutic targets for diabetes-associated HFpEF.Ph.D