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

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 hypertrophy, and reduced cardiac output. This suggests a different role for UCP2 in right and left ventricular adaptation to pressure overload. To clarify this situation in more detail UCP2-/- and wild type (WT) mice were exposed to pulmonary arterial banding (PAB). METHODS AND RESULTS Mice were analyzed (hemodynamics, morphometry, and echocardiography) three weeks after PAB or sham surgery. Myocytes and non-myocytes were isolated and analyzed 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 analyzed to investigate the role of UCP2 for reactive oxygen species (ROS) production. UCP2 mRNA was 2.7-fold stronger expressed in right ventricular myocytes than in left ventricular myocytes and stronger expressed in non-myocytes compared to myocytes. Three weeks after PAB, cardiac output was reduced in WT but preserved in UCP2-/- mice. UCP2-/- had increased right ventricular wall thickness, but lower right ventricular 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 WT 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 behavior of non-myocytes (fibroblasts).