Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is the most common cause of PH worldwide, and at present, it has no proven effective therapies. Previously, we have found convincing evidence that PH-HFpEF-regulating sirtuin-3 (SIRT3) is predominantly decreased in the skeletal muscle. During the past grant period, we found a new endocrine signaling axis that links depressed skeletal muscle SIRT3 to production/secretion of signaling molecules that interact with pulmonary vasculature in PH-HFpEF. However, underlying mechanisms by which skeletal muscle SIRT3-mediated scretome regulates pathological changes in pulmonary vasculature are not well-understood at present. Based on a mass spectrometry-based plasma proteomics approach, our new data show that 2-microglobulin (B2M) is present at higher levels in patients with PH-HFpEF. Both circulating and skeletal muscle levels of B2M are markedly increased in mice with skeletal muscle SIRT3 deficiency. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients also show higher B2M levels with increased disease severity. Treatment with B2M recombinant protein reduces expression of WW domain-containing oxidoreductase (WWOX), which plays a role in repressing cell proliferation, in PASMCs. B2M treatment also increases expression of canopy fibroblast growth factor signaling regulator 2 (CNPY2), an unfolded protein response (UPR) initiator known to induce excessive angiogenesis and proliferation, in PAECs. While B2M treatment increases PAECs migration/proliferation and media conditioned by CNPY2-overexpressed PAECs reduces WWOX in PASMCs, the role of PAECs CNPY2 in PH-HFpEF remains elusive. Thus, we hypothesize that skeletal muscle-secreted B2M acts as an endocrine signaling molecule which induces remote pulmonary vascular remodeling via dysregulating PAECs CNPY2 and PASMCs WWOX. Specific Aim 1 will determine whether skeletal muscle B2M is an important signaling molecule affecting multiple pulmonary vascular pathophenotypes. Using wild-type and skeletal muscle-specific B2m KO mice, with or without high-fat feeding (HFD), which induces a PH-HFpEF phenotype, we will characterize the contribution of skeletal muscle B2M in PH-HFpEF. In Aim 2, we will determine the role of PAECs CNPY2 in pulmonary vascular remodeling and PH-HFpEF with EC-specific Cnpy2 KO mice. Specific Aim 3 will use plasma and muscle biopsies of patients with PH-HFpEF or HFpEF alone collected from biobanks and Phase II clinical trials to evaluate whether B2M can be a relevant biomarker of PH-HFpEF severity and prognosis. Inducible pluripotent stem cell (iPSC)-derived ECs of PH-HFpEF patients will also be used to evaluate clinical relevance of CNPY2. We expect that successful execution of the proposed research plan would provide new mechanistic understanding of PH-HFpEF pathogenesis and aid in providing important information to guide future research towards development of therapeutic approaches for the presentably untreatable PH-HFpEF.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
