Rationale: Diabetes mellitus is often associated with cardiovascular complications, which is the leading cause of morbidity and mortality among patients with diabetes mellitus, but little is known about the mechanism that connects diabetes mellitus to the development of cardiovascular dysfunction. Objective: We aim to elucidate the mechanism underlying hyperglycemia-induced cardiac dysfunction on a well-established db/db mouse model for diabetes mellitus and diabetic complications that lead to heart failure. Methods and Results: We first profiled the expression of microRNAs (miRNAs) by microarray and quantitative reverse transcription polymerase chain reaction on db/db mice and identified miR-320 as a key miRNA associated with the disease phenotype. We next established the clinical relevance of this finding by showing the upregulation of the same miRNA in the failing heart of patients with diabetes mellitus. We demonstrated the causal role of miR-320 in inducing diabetic cardiomyopathy, showing that miR-320 overexpression exacerbated while its inhibition improved the cardiac phenotype in db/db mice. Unexpectedly, we found that miR-320 acts as a small activating RNA in the nucleus at the level of transcription. By chromatin immunoprecipitation sequencing and chromatin immunoprecipitation quantitive polymerase chain reaction analysis of Ago2 (argonaute RISC catalytic component 2) and RNA polymerase II in response to miR-320 induction, we identified CD36 (fatty acid translocase) as a key target gene for this miRNA and showed that the induced expression of CD36 is responsible for increased fatty acid uptake, thereby causing lipotoxicity in the heart. Conclusions: These findings uncover a novel mechanism for diabetes mellitus–triggered cardiac dysfunction, provide an endogenous case for small activating RNA that has been demonstrated to date only with synthetic RNAs in transfected cells, and suggest a potential strategy to develop a miRNA-based therapy to treat diabetes mellitus–associated cardiovascular complications.

Previously, we found that the miR-217 expression level was increased in hearts from chronic heart failure (CHF) patients by using miRNA profile analysis. This study aimed to explore the role of miR-217 in cardiac dysfunction. Heart tissue samples from CHF patients were used to detect miR-217 expression levels. A type 9 recombinant adeno-associated virus (rAAV9) was employed to manipulate miR-217 expression in mice with thoracic aortic constriction (TAC)-induced cardiac dysfunction. Cardiac structure and function were measured by echocardiography and invasive pressure-volume analysis. The expression levels of miR-217 were increased in hearts from both CHF patients and TAC mice. Overexpression of miR-217 in vivo aggravated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction, whereas miR-217-TUD-mediated downregulation of miR-217 reversed these effects. PTEN was predicted and validated as a direct target of miR-217, and re-expression of PTEN attenuated miR-217-mediated cardiac hypertrophy and cardiac dysfunction. Importantly, cardiomyocyte-derived miR-217-containing exosomes enhanced proliferation of fibroblasts in vitro. All of these findings show that miR-217 participates in cardiac hypertrophy and cardiac fibrosis processes through regulating PTEN, which suggests a promising therapeutic target for CHF.

BackgroundDiabetes is a leading cause of mortality and morbidity across the world. Over 50% of deaths among diabetic patients are caused by cardiovascular diseases. Cardiac diastolic dysfunction is one of the key early signs of diabetic cardiomyopathy, which often occurs before systolic dysfunction. However, no drug is currently licensed for its treatment.MethodsType 9 adeno-associated virus combined with cardiac Troponin T promoter were employed to manipulate miR-21 expression in the leptin receptor-deficient (db/db) mice. Cardiac structure and functions were measured by echocardiography and hemodynamic examinations. Primary cardiomyocytes and cardiomyocyte cell lines were used to perform gain/loss-of-function assays in vitro.ResultsWe observed a significant reduction of miR-21 in the diastolic dysfunctional heart of db/db mice. Remarkably, delivery of miR-21 efficiently protected against the early impairment in cardiac diastolic dysfunction, represented by decreased ROS production, increased bioavailable NO and relieved diabetes-induced cardiomyocyte hypertrophy in db/db mice. Through bioinformatic analysis and Ago2 co-immunoprecipitation, we identified that miR-21 directly targeted gelsolin, a member of the actin-binding proteins, which acted as a transcriptional cofactor in signal transduction. Moreover, down-regulation of gelsolin by siRNA also attenuated the early phase of diabetic cardiomyopathy.ConclusionOur findings reveal a new role of miR-21 in attenuating diabetic cardiomyopathy by targeting gelsolin, and provide a molecular basis for developing a miRNA-based therapy against diabetic cardiomyopathy.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0767-z) contains supplementary material, which is available to authorized users.