MicroRNA-140 is elevated and mitofusin-1 is downregulated in the right ventricle of the Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension.

Abstract

Joshi SR, Dhagia V, Gairhe S, Edwards JG, McMurtry IF, Gupte SA. MicroRNA-140 is elevated and mitofusin-1 is downregulated in the right ventricle of the Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 311: H689 -H698, 2016. First published July 15, 2016 doi:10.1152/ajpheart.00264.2016.-Heart failure, a major cause of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), is an outcome of complex biochemical processes. In this study, we determined changes in microRNAs (miRs) in the right and left ventricles of normal and PAH rats. Using an unbiased quantitative miR microarray analysis, we found 1) miR- 21-5p, miR-31-5 and 3p, miR-140-5 and 3p, miR-208b-3p, miR-221-3p, miR-222-3p, miR-702-3p, and miR-1298 were upregulated (Ͼ2-fold; P Ͻ 0.05) in the right ventricle (RV) of PAH compared with normal rats; 2) miR-31-5 and 3p, and miR-208b-3p were upregulated (Ͼ2-fold; P Ͻ 0.05) in the left ventricle plus septum (LVϩS) of PAH compared with normal rats; 3) miR-187-5p, miR-208a-3p, and miR-877 were downregulated (Ͼ2-fold; P Ͻ 0.05) in the RV of PAH compared with normal rats; and 4) no miRs were up-or downregulated with Ͼ2-fold in LVϩS compared with RV of PAH and normal. Upregulation of miR-140 and miR-31 in the hypertrophic RV was further confirmed by quantitative PCR. Interestingly, compared with control rats, expression of mitofusin-1 (MFN1), a mitochondrial fusion protein that regulates apoptosis, and which is a direct target of miR-140, was reduced in the RV relative to LVϩS of PAH rats. We found a correlation between increased miR-140 and decreased MFN1 expression in the hypertrophic RV. Our results also demonstrated that upregulation of miR-140 and downregulation of MFN1 correlated with increased RV systolic pressure and hypertrophy. These results suggest that miR-140 and MFN1 play a role in the pathogenesis of PAH-associated RV dysfunction.Listen to this article's corresponding podcast at http://ajpheart. podbean.com/e/mir140-and-right-heart-hypertrophy/. miR; heart; hypertrophy; heart failure; pulmonary; hypertension; lungs; rats THE PATHOPHYSIOLOGY of pulmonary arterial hypertension (PAH) is heterogeneous. In PAH, pulmonary vascular resistance and arterial pressure are increased, and the right ventricle (RV) is hypertrophied in response to increased afterload/pressure overload. Increased afterload in PAH leads to myocardial dysfunction, tricuspid regurgitation with progressive annular dilatation, and ultimately RV failure (67).Heart failure, a major cause of mortality in PAH patients (4, 5), is a complex syndrome. In the failing hearts, oxidative stress is increased and the rate of cardiomyocyte apoptotic and autophagic death is augmented (6,49,51,60,62). Activation of these processes causes myocardial stiffening, dilatation, and loss of contractility (49, 51). However, the mechanisms that regulate apoptosis and autophagy in this complex pathology are unclear and are an area under investigation.MicroRNAs (miRs) are a class of small no...

Circulating miRNA Expression Profiling and Target Prediction in Patients Receiving Dexmedetomidine

“…These results indicate that miR-140 plays a role in the pathogenesis of pulmonary artery hypertension-associated right ventricular dysfunction [22]. Another study found that miR-140-3p was one of upregulated miRNAs in afterload-enhancement-induced pathological hypertrophy in engineered heart tissue [9].…”

Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement

“…Studies of isolated cardiomyocytes and ECs (ideally from animal models of severe RVF and/or well-phenotyped human samples) would provide novel mechanistic insights in RV cell death initiation and progression. The contribution of endoplasmic reticulum stress, mitochondrial fusion and mitophagy (249), autophagy (245)(246)(247), and nonapoptotic types of cell death to RVF development requires further study. Identification and validation of cardiac troponins as markers of cardiomyocyte death (rather than damage) would move the field forward.…”

Effects of miRNAs on myocardial apoptosis by modulating mitochondria related proteins

“…Under H 2 O 2 and DOX treatment, ectopic miR‐140 expression can induce mitochondrial fission and apoptosis through inhibition of Mfn1 translation . Further, the elevated miR‐140 and decreased Mfn1 also play crucial roles in the process of heart failure as a result of pulmonary arterial hypertension (PAH) . Additionally, miR‐214 level was enhanced and inhibited its target Mfn2 level resulting in cardiac fibroblast (CF) proliferation and collagen synthesis induced by isoproterenol (ISO) .…”

“…35 Further, the elevated miR-140 and decreased Mfn1 also play crucial roles in theprocessofheartfailureasaresultofpulmonaryarterialhypertension(PAH). 36 Additionally,miR-214levelwasenhancedandinhibited its target Mfn2 level resulting in cardiac fibroblast (CF) proliferation and collagen synthesis induced by isoproterenol (ISO). 37 Therefore, themiR-140-Mfn1andmiR-214-Mfn2axes,respectively,playcritical rolesinthepathogenesisofcardiacremodelling.…”