Specific Mechanisms underlying Right Heart Failure : The Missing Upregulation of Superoxide Dismutase-2 and Its Decisive Role in Antioxidative Defense

Schreckenberg, R. and da Costa Rebelo, M. and Deten, A. and Weber, M. and Rohrbach, S. and Pipicz, Márton and Csonka, Csaba and Ferdinandy, Péter (2015) Specific Mechanisms underlying Right Heart Failure : The Missing Upregulation of Superoxide Dismutase-2 and Its Decisive Role in Antioxidative Defense. ANTIOXIDANTS & REDOX SIGNALING, 23 (15). pp. 1220-1232. ISSN 1523-0864

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Abstract

AIMS: Research into right ventricular (RV) physiology and identification of pathomechanisms underlying RV failure have been neglected for many years because function of the RV is often considered to be less important for overall hemodynamics and maintenance of blood circulation. In view of this, the present study focuses on identifying specific adaptive mechanisms of the right and left ventricle (LV) during a state of chronic nitric oxide (NO) deficiency, one of the main causes of cardiac failure. NO deficiency was induced in rats by L-NAME feeding over a four weeks period. The cardiac remodeling was then characterized separately for the RV/LV using qRT-PCR, histology, and functional measurements. RESULTS: Only the RV underwent remodeling that corresponded morphologically and functionally with the pattern of dilated cardiomyopathy. Symptoms in the LV were subtle and consisted primarily of moderate hypertrophy. A massive increase in reactive oxygen species (ROS) (+4.5+/-0.8 fold, vs. control) and a higher degree of oxidized tropomyosin (+46+/-4% vs. control) and peroxynitrite (+32+/-2% vs. control) could be identified as the cause of both RV fibrosis and contractile dysfunction. The expression of superoxide dismutase-2 was specifically increased in the LV by 51+/-3% and prevented the ROS increase and the corresponding structural and functional remodeling. INNOVATION: This study identified the inability of the RV to increase its antioxidant capacity as an important risk factor for developing RV failure. CONCLUSION: Unlike the LV, the RV did not display the necessary adaptive mechanisms to cope with increased oxidative stress during a state of chronic NO deficiency.

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