Protection against pressure overload-induced right heart failure by uncoupling protein 2 silencing

Abstract

Aims The role of uncoupling protein 2 (UCP2) in cardiac adaptation to pressure overload remains unclear. In a classical model of left ventricular pressure overload genetic deletion of UCP2 (UCP2 −/− ) protected against cardiac hypertrophy and failure. However, in UCP2 −/− mice increased proliferation of pulmonary arterial smooth muscle cells induces mild pulmonary hypertension, right ventricular (RV) hypertrophy, and reduced cardiac output. This suggests a different role for UCP2 in RV and left ventricular adaptation to pressure overload. To clarify this situation in more detail UCP2 −/− and wild-type mice were exposed to pulmonary arterial banding (PAB). Methods and results Mice were analysed (haemodynamics, morphometry, and echocardiography) 3 weeks after PAB or sham surgery. Myocytes and non-myocytes were isolated and analysed separately. Cell shortening of myocytes and fura-2 loading of cardiomyocytes were used to characterize their function. Brd assay was performed to study fibroblast proliferation. Isolated mitochondria were analysed to investigate the role of UCP2 for reactive oxygen species (ROS) production. UCP2 mRNA was 2.7-fold stronger expressed in RV myocytes than in left ventricular myocytes and stronger expressed in non-myocytes compared with myocytes. Three weeks after PAB, cardiac output was reduced in wild type but preserved in UCP2 −/− mice. UCP2 −/− had increased RV wall thickness, but lower RV internal diameters and displayed a significant stronger fibrosis. Cardiac fibroblasts from UCP2 −/− had reduced proliferation rates but higher collagen-1 expression. Myocytes isolated from mice after PAB banding showed preserved function that was further improved by UCP2 −/− . Mitochondrial ROS production and respiration was similar between UCP2 −/− or wild-type hearts. Conclusion Despite a mild pulmonary hypertension in UCP2 −/− mice, hearts from these mice are well preserved against additional pressure overload (severe pulmonary hypertension). This—at least in part—depends on different behaviour of non-myocytes (fibroblasts).

Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia

“…Uncoupling proteins (UCPs), in contrast, are mitochondrial inner membrane proteins that act as proton leaks, thereby dissipating the proton gradient. Uncoupling protein 2 ( Ucp2 ) has previously been shown to be instrumental for protection against pressure overload‐induced right heart failure . Here, we found Ucp2 specifically up‐regulated in the AOX I/R group (Figure E).…”

“…Uncoupling protein 2 (Ucp2) has previously been shown to be instrumental for protection against pressure overload-induced right heart failure. 60 Here, we found Ucp2 specifically up-regulated in the AOX I/R group ( Figure 4E). Finally, heart failure due to apoptotic loss of cardiomyocytes has been long discussed.…”

Alterations in Glucose Metabolism During the Transition to Heart Failure: The Contribution of UCP-2

“…In a previous study, we found that UCP-2 expression in cardiomyocytes from mice is low compared to non-myocytes and that a deficiency of UCP-2 is accompanied by improved fibrotic responsiveness in the right ventricle, which preserves cardiac output under pressure overload [4]. However, the situation in a pressure-overloaded LV may be different as fibrosis contributes to the development of LV diastolic dysfunction [18].…”

“…Protein samples were loaded on NuPAGE Bis-Tris Precast gels (10%; Life Technology, Darmstadt, Germany) and subsequently transferred onto nitrocellulose membranes. The expression of UCP-2 was analyzed with an antibody (also kindly provided by Prof. Dr. E. Pohl), whose specificity was evaluated before [4,17]. The Glut-4 antibody was kindly provided by Samuel W. Cushman (NIH, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Montgomery, MD, USA).…”

“…We showed recently that in mice hearts, UCP-2 is mainly expressed in non-myocytes. Moreover, the absence of UCP-2 in mice improved cardiac adaptation to pulmonary arterial hypertension, mainly by increased fibrosis [4]. However, it remains elusive whether UCP-2 is also preferentially expressed in non-myocytes in other mammalians.…”