Protective effects of calcyclin-binding protein against pulmonary vascular remodeling in flow-associated pulmonary arterial hypertension

Abstract

Background Pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) is recognized as a cancer-like disease with a proliferative and pro-migratory phenotype in pulmonary artery smooth muscle cells (PASMCs). Calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) has been implicated in the progression of various cancers; however, it has not been previously studied in the context of CHD-PAH. Here, we aimed to examine the function of CacyBP/SIP in CHD-PAH and explore its potential as a novel regulatory target for the disease. Methods The expression of CacyBP/SIP in PASMCs was evaluated both in the pulmonary arterioles of patients with CHD-PAH and in high-flow-induced PAH rats. The effects of CacyBP/SIP on pulmonary vascular remodeling and PASMC phenotypic switch, proliferation, and migration were investigated. LY294002 (MedChemExpress, NJ, USA) was used to block the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway to explore changes in PASMC dysfunction induced by low CacyBP/SIP levels. Hemodynamics and pulmonary arterial remodeling were further explored in rats after short-interfering RNA-mediated decrease of CacyBP/SIP expression. Results CacyBP/SIP expression was markedly reduced both in the remodeled pulmonary arterioles of patients with CHD-PAH and in high-flow-induced PAH rats. Low CacyBP/SIP expression promoted hPASMC phenotypic switch, proliferation, and migration via PI3K/AKT pathway activation. Our results indicated that CacyBP/SIP protected against pulmonary vascular remodeling through amelioration of hPASMC dysfunction in CHD-PAH. Moreover, after inhibition of CacyBP/SIP expression in vivo, we observed increased right ventricular hypertrophy index, poor hemodynamics, and severe vascular remodeling. Conclusions CacyBP/SIP regulates hPASMC dysfunction, and its increased expression may ameliorate progression of CHD-PAH.

Cellular taxonomy of the preleukemic bone marrow niche of acute myeloid leukemia

“…We identified chemokine Cxcl9 was upregulated in PTD;ITD ECs compared to WT (∼1.4-fold increase, P<0.01 ), which has been shown to be induce chemotaxis, and disrupt endothelial barrier function previously 21 . Ccn2 (∼ 2-fold decrease, P<0.01 ), known to regulate endothelial cell adhesion to pericytes 22 , and Cacybp (∼1.3-fold decrease, P<0.01 ), previously shown inhibit vascular remodeling 23 , were decreased in preleukemic PTD; ITD ECs compared to WT ECs (Figure 3D), confirming vascular remodeling of BM niche in pre-leukemic PTD;ITD BM.…”

The Communal Pathogenesis, Autophagy Mechanism and Potential Therapeutic Targets in Dilated Cardiomyopathy and Viral Myocarditis

“…Cardiomyocyte-speci c SOCS1 overexpression inhibited the activation of the JAK-STAT signaling pathway, improved viral replication in virus-infected cardiomyocytes, cardiomyopathy, and increased mortality in coxsackievirus-infected mice [26]. PI3K-Akt signaling pathway is a star pathway in medical research, which plays an important role in regulating a variety of different cellular functions, including metabolism, growth, proliferation, survival, transcription, and protein synthesis [27,28]. The role of this pathway in the direction of autophagy regulation has also been extensively studied.…”

Pulmonary arterial hypertension related to congenital heart disease with a left-to-right shunt: phenotypic spectrum and approach to management

“…These factors, which include sequences of non-coding RNA, micro-RNA and protein polymorphisms, are still poorly understood and a comprehensive appraisal of this topic is beyond the scope of this review ( 22 ). Recent mechanistic work has shown a link between signals regulating cellular proliferation and differentiation, and the biology of pulmonary smooth muscle cells ( 23 ). Different levels of expression of proteins involved in smooth muscle cell proliferation correlate with the severity of PVD in animal models of flow-associated PAH; such proteins may have a protective role against vascular remodeling in the presence of a left-right shunt ( 23 ).…”

“…Recent mechanistic work has shown a link between signals regulating cellular proliferation and differentiation, and the biology of pulmonary smooth muscle cells ( 23 ). Different levels of expression of proteins involved in smooth muscle cell proliferation correlate with the severity of PVD in animal models of flow-associated PAH; such proteins may have a protective role against vascular remodeling in the presence of a left-right shunt ( 23 ). These data shed new light on the pathogenesis of PAH-CHD, moving away from the traditional view that this is a condition triggered exclusively by hemodynamics.…”