Calpain Activates Intracellular TGF-beta1 in Pulmonary Hypertension

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DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling that is associated with accumulation of extracellular matrix, including collagen, and vascular cell proliferation, medial and adventitial thickening, occlusive neointima, and complex plexiform lesions, leading to obliteration of precapillary pulmonary arteries and sustained elevation of pulmonary arterial pressure. PDGF, EGF, VEGF, and TGF?1 participate in the process of pulmonary vascular remodeling. We recently reported for the first time that global knockout of calpain prevents pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension and that the calpain inhibitor MDL28170 prevents the progression of established pulmonary hypertension induced by monocrotaline. Calpain is a family of calcium-dependent non-lysosomal neutral cysteine endopeptidases that act via limited proteolysis of substrate proteins in mammalian cells including pulmonary vascular cells. Calpain is the downstream signal transduction molecule of PDGF, EGF and VEGF, and mediates PDGF- and EGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells (PASMCs) and VEGF-induced angiogenesis of pulmonary artery endothelial cells (PAECs). We have recently found that calpain cleaves and activates TGF?1 and that an intracrine TGF? signal pathway exists in PASMCs. To validate the role of calpain in pulmonary vascular remodeling in animal models, we will take advantage of the human lung tissues provided by the Pulmonary Hypertension Breakthrough Initiative (PHBI) and test our novel hypothesis that calpain activates intracellular TGF?1 in pulmonary vascular remodeling associated with IPAH. To test this hypothesis, we propose a multidisciplinary approach focusing on the following specific aims: #1 is to determine whether calpain inhibition prevents or attenuates collagen synthesis and proliferation of PASMCs and PAECs from patients with idiopathic pulmonary arterial hypertension (IPAH); #2 is to determine whether calpain activates intracellular TGF?1 in PASMCs and PAECs from patients with IPAH. Proof of regulation of collagen synthesis and proliferation by calpain in pulmonary vascular cells may lead to development of new pharmacologic strategies that will target calpain in pulmonary vascular remodeling associated with pulmonary hypertension.