Abstract
Purpose Adiponectin is an anti-inflammatory fat-derived adipocytokine that plays a fundamental role in energy homeostasis. Previous data demonstrate different modulation of adiponectin and its receptors in chronic heart failure (CHF), consistent with the hypothesis of a compensatory role for adiponectin in CHF. Our aim was to determine the mechanisms underlying the different regulation of the adiponectin receptors in CHF. Methods and Materials Expression of adiponectin receptors (AdipoR1; AdipoR2) was assessed by real-time PCR and immunohistochemistry on myocardium of patients with terminal CHF undergoing heart transplantation. All patients gave informed consent. Biopsies (n=40) of the explanted hearts were obtained and the expression of AdipoR1, AdipoR2, and miRNA150 was analyzed by means of qPCR. A group consisting of heart muscle biopsies (n=8) from autopsies of heart-healthy subjects served as control. Results Knock-down of DICER-expression by a specific siRNA resulted in an enhanced expression of adiponectin receptor 2, whereas receptor 1 remained unchanged. These results indicate that only adiponectin receptor 2 is influenced by miRNA-mediated gene silencing. Moreover, down-regulation of ADIPOR2 mRNA by approximately 60% was found in cells transiently transfected with premiR-150 precursor molecules as compared to non-sense premiR control. In accordance, ADIPOR2 protein expression was decreased in miR-150 overexpressing cells. To verify the myocardial expression of miR-150, we determined miR-150 levels by qPCR. miR-150 was substantially expressed in both normal and CHF myocardium (overall mean C q 26.5±0.1), with the expression being 1.7-fold (p=0.001, n=12) higher in CHF. Conclusions Disregulation of cardiac miR-150 expression counteracts the up-regulation of ADIPOR2 in cardiac tissue and prevents an adequate adiponectin response. Relieve of this adiponectin resistant state by antagonizing the repressive effect of miR-150, for example by use of antagomirs, could therefore help to restore the beneficial cardioprotective action of adiponectin.
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