2011肺动脉高压发生的分子机制(研究生讲座).pptVIP

* Proposed mechanisms involved in angiopoietin-1 (Ang-1)-mediated pulmonary vascular remodeling. Ang-1 released from pulmonary artery smooth muscle cells (SMC) binds toTIE2 on the surface membrane of pulmonary arterial endothelial cells (EC) and leads to an increase in 5-HT production and downregulation of BMP-RI gene in EC. 5-HT released from EC then interacts with 5-HT receptors (5-HTR) and transporters (5-HTT) causing SMC contraction by increasing [Ca2+]cyt and stimulating SMC proliferation by activating ERK/MAPK pathway. Downregulated BMP-RI gene in EC would lead to inhibition of BMP-BMP-R-Smad signaling pathway, which induces EC proliferation and inhibits SMC apoptosis. Therefore, overexpression of Ang-1 in SMC triggers pulmonary vasoconstriction and stimulates SMC/EC proliferation by both autocrine and paracrine mechanisms. * In native cells, functional KV channels are heteromultimeric tetramers composed of pore-forming ? and regulatory ? subunits. In PASMC from IPAH patients, the amplitude of IK(V) and the mRNA/protein expression level of KV channel ? subunits (e.g., KV1.2 and KV1.5) are both significantly decreased in comparison to PASMC from patients with non-pulmonary hypertension (NPH) cardiopulmonary diseases and SPH (Yuan et al., 1998a,b). These decreases translate to a more depolarized Em in IPAHP ASMC. Ion channels In IPAH, the pulmonary artery smooth muscle cells are in an abnormally depolarized state due to increased cytosolic Ca2+. This depolarization apparently results in vasoconstriction, related to the primary dysfunction and downregulation of the voltage-gated K+ channels (Kv) [78,79]. Kv channels are inhibited by hypoxia and cause hypoxic pulmonary vasoconstriction [80]. Vasoconstriction has been linked to defects in the function or expression of K+ channels and to endothelial dysfunction. A specific polymorphism of Kv1.5 channel gene associated with a predilection to channel depletion has recently been described [81]. Therefore Kv channel dy