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A2442 - Role of Skeletal Muscle SIRT3 in PH-HFpEF
Author Block: Y. Lai1, K. Noda2, J. Baust1, T. Bachman1, D. Goncharov1, E. A. Goncharova3, A. L. Mora4, M. T. Gladwin5; 1Vascular Medicine Institute, Pittsburgh, PA, United States, 2Department of Cardiothoracic Surgery, Pittsburgh, PA, United States, 3Medicine, Univ of Pittsburgh -Sch of Med, Pittsburgh, PA, United States, 4Vascular Med Inst., Univ of Pittsburgh Sch of Med, Pittsburgh, PA, United States, 5UPMC Montefiore NW 628, Univ of Pittsburgh, Pittsburgh, PA, United States.
Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF, CpcPH; WHO Group 2) is the most common cause of PH worldwide, imposing an economic burden of about 8 billion dollars annually in the United States alone. At present, no specific effective therapy has been identified, mainly due to the fact that major pathways involved in the regulation of PH-HFpEF are still not well understood. We have recently reported that nitrite and metformin activate skeletal muscle and pulmonary vascular SIRT3-AMPK signaling pathway to modulate PH in the setting of HFpEF. In order to determine a possible role for cross-talk between the skeletal muscle and pulmonary vasculature we have evaluated skeletal muscle specific SIRT3 knockout (SIRT3skm-/-) mice. Our preliminary data show that the absence of SIRT3 in skeletal muscle leads to a reduction of the pulmonary vascularity, accompanied by increased vascular remodeling and higher pulmonary pressures, indicating a critical role of skeletal muscle SIRT3 in pulmonary vascular remodeling and PH-HFpEF. Based on global mass spectrometry-based comparative secretome analysis of cultured C2C12 myotubes, we found that skeletal muscle SIRT3 deficiency enhances the secretion of lysyl oxidase homolog 2 (LOXL2), a matrix enzyme known to promote cross-linking of collagen, and gremlin-1 (Grem1), a bone morphogenetic protein (BMP) antagonist known to induce excessive proliferation. Both LOXL2 and Grem1 levels are higher in plasma of patients with PH-HFpEF, rat model of experimental PH-HFpEF, and skeletal muscle-specific Sirt3 KO mice. Finally, our data show that along with increased LOXL2 levels, periarteriolar collagen cross-linking is increased in SIRT3skm-/- mice compared to the age-matched wild-type (WT) mice. These studies suggest that there may be a skeletal muscle-lung vasculature crosstalk in PH-HFpEF through endocrine LOXL2 and Grem1 signaling, and identify skeletal muscle SIRT3, along with its downstream LOXL2 and Grem1, as potential molecular targets for the treatment of PH-HFpEF.