Suppression of Fibulin 5 Attenuated Pulmonary Arterial Hypertension Associated with Congenital Heart Disease via Mitigating Pulmonary Arterial Smooth Muscle Cell Dysfunction

Abstract Backgrounds: The specific molecular pathogenesis of pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) and the reversal still remain elusive. Fibulin 5 was involved in the regulation of cardiovascular system while little is known about the expression and functions of fibulin 5 in the development of CHD-PAH. This study aimed to investigate the role of fibulin 5 in the pathogenesis of the disease. Methods Lung samples were obtained both from patients with CHD-PAH and aortocaval shunt-associated PAH rat models. TGF-β1was used to induce human pulmonary artery smooth muscle cells (hPASMCs) dysfunction and lentiviruses were responsible for alteration of fibulin 5 expression. In an effort to explore the specific role of fibulin 5, an inhibitor of phosphatidylinositol-3-kinases (PI3K) /protein-serine-threonine kinase (AKT) which was defined as the TGF-β1-related downstream signaling was applied for further exploration. Results Fibulin 5 was pronouncedly elevated in the PASMCs of the remodeled pulmonary arterioles from patients with CHD-PAH and shunt-associated PAH rats. We found that over-expression of fibulin 5 could promote hPASMCs dysfunction induced by TGF-β1 and it could be reversed by the PI3K/AKT inhibitor LY294002 suggesting the essential role of TGF-β1/PI3K/AKT signaling activation in phenotypic switch, proliferation and migration of PASMCs. Moreover, an adeno-associated virus vector encoding fibulin 5 by intratracheally instillation with rats improve the hemodynamic parameters in shunt-associated PAH rats and its related pulmonary artery remodeling. Conclusion Over-expression of fibulin 5 could significantly promote hPASMCs dysfunction and pulmonary artery remodeling via reinforcing TGF-β1/PI3K/AKT signaling activation, which highlighted the potential valuable pharmacological target for the treatment of CHD-PAH.Fibulin 5 was over-expressed in PAHInhibition of fibulin 5 attenuated PAH