MiR-30 promotes fatty acid beta-oxidation and endothelial cell dysfunction and is a circulating biomarker of coronary microvascular dysfunction in pre-clinical models of diabetes

Abstract

Background Type 2 diabetes (T2D) is associated with coronary microvascular dysfunction, which is thought to contribute to compromised diastolic function, ultimately culminating in heart failure with preserved ejection fraction (HFpEF). The molecular mechanisms remain incompletely understood, and no early diagnostics are available. We sought to gain insight into biomarkers and potential mechanisms of microvascular dysfunction in obese mouse (db/db) and lean rat (Goto-Kakizaki) pre-clinical models of T2D-associated diastolic dysfunction. Methods The microRNA (miRNA) content of circulating extracellular vesicles (EVs) was assessed in T2D models to identify biomarkers of coronary microvascular dysfunction/rarefaction. The potential source of circulating EV-encapsulated miRNAs was determined, and the mechanisms of induction and the function of candidate miRNAs were assessed in endothelial cells (ECs). Results We found an increase in miR-30d-5p and miR-30e-5p in circulating EVs that coincided with indices of coronary microvascular EC dysfunction (i.e., markers of oxidative stress, DNA damage/senescence) and rarefaction, and preceded echocardiographic evidence of diastolic dysfunction. These miRNAs may serve as biomarkers of coronary microvascular dysfunction as they are upregulated in ECs of the left ventricle of the heart, but not other organs, in db/db mice. Furthermore, the miR-30 family is secreted in EVs from senescent ECs in culture, and ECs with senescent-like characteristics are present in the db/db heart. Assessment of miR-30 target pathways revealed a network of genes involved in fatty acid biosynthesis and metabolism. Over-expression of miR-30e in cultured ECs increased fatty acid β-oxidation and the production of reactive oxygen species and lipid peroxidation, while inhibiting the miR-30 family decreased fatty acid β-oxidation. Additionally, miR-30e over-expression synergized with fatty acid exposure to down-regulate the expression of eNOS, a key regulator of microvascular and cardiomyocyte function. Finally, knock-down of the miR-30 family in db/db mice decreased markers of oxidative stress and DNA damage/senescence in the microvascular endothelium. Conclusions MiR-30d/e represent early biomarkers and potential therapeutic targets that are indicative of the development of diastolic dysfunction and may reflect altered EC fatty acid metabolism and microvascular dysfunction in the diabetic heart.

Targeting miR-30d reverses pathological cardiac hypertrophy

“…The expression of miR-30d has been shown to be increased in diabetes. miR-30d was found to be increased in endothelial cells of the left ventricle of db/db mice, but not other organs; 36 increased in lactating mothers with type 1 diabetes; 37 increased in the serum of patients with type 2 diabetes. 38 Second, miR-30d was reported to be a glucose-regulated miRNA and could induce insulin transcription in pancreatic β-cells.…”

“… 42 In addition, miR-30d was reported to promote fatty acid beta-oxidation in cardiac endothelium in type 2 diabetes mice. 36 Thus, the excessive generation of reactive lipid intermediates in cardiomyocytes may induce lipotoxicity. Without the diabetes injury, the pro-fatty acid beta-oxidation of miR-30d may benefit cardiomyocytes.…”

Cardiovascular signatures of COVID-19 predict mortality and identify barrier stabilizing therapies

“…We considered miRNAs within the top 50% of abundance and cross-examined the differential expression between both survivors and non-survivors of COVID-19 as well as SARS-CoV-2 severe negatives. Additionally, we took into consideration existing biological relevance, thereby specifically analyzing miR-1, which is associated with myocardial injury, 70 , 71 miR-199a-3p which has been shown to be cardioprotective, 72 miR-181a-5p which has been shown to restrict vascular inflammation, 73 along with members of the miR-30 family which are enriched in ECs and capable of modulating inflammation, 74 , 75 , 76 as well miR-339-3p and miR-6080 which were among the highest differentially expressed. Univariable hazard ratios and log-rank P-values were generated to determine the relationship of the miRNA expression measured in plasma with mortality.…”

Exosomal microRNAs miR-30d-5p and miR-126a-5p Are Associated with Heart Failure with Preserved Ejection Fraction in STZ-Induced Type 1 Diabetic Rats

“…We selected 12 miRNAs associated with diabetic HF. The initial selection of miRNAs in our panel were miR-1 [ 28 , 29 ], miR-21 [ 30 ], miR-29a [ 31 ], miR-30d [ 32 , 33 ], miR-34a [ 34 ], miR-126a [ 35 ], miR-143 [ 36 ], miR-145 [ 37 ], miR-195 [ 38 ], miR-206 [ 39 ], miR-320 [ 39 ] and miR-378 [ 40 ]. We found that the expression of all miRNAs was significantly lower in HFpEF diabetic hearts than in controls ( Figure 5 A–L).…”