CTRP9 Ameliorates Pulmonary Arterial Hypertension Through Attenuating Inflammation and Improving Endothelial Cell Survival and Function

Abstract

Endothelial dysfunction and inflammation are believed to be 2 primary instigators of pulmonary arterial hypertension (PH). C1q/TNF-related protein 9 (CTRP9) plays important roles in anti-inflammation and improvement of epithelial function. However, the role of CTRP9 in the progression of PH remains still unclear. In this study, the role and mechanism of CTRP9 in the PH progression were explored. First, serum CTRP9 contents and CTRP9 mRNA expression in the pulmonary artery epithelial cells from patients with PH were detected. Our data on enzyme-linked immunosorbent assay and real-time quantitative Polymerase Chain Reaction showed that CTRP9 mRNA and protein content were markedly downregulated in the patients with PH. Then the pcDNA-CTRP9 expression vector or CTRP9 siRNA was transfected into the primary pulmonary artery epithelial cells from the patients with PH in vitro. CTRP9 overexpression significantly improved endothelial NOS protein expression and reduced the secretion of endothelin-1 (ET-1) and matrix metalloproteinase-2 (MMP-2), whereas knockdown of CTRP9 sharply reduced eNOS protein expression and promoted the secretion of ET-1 and MMP-2 in the cultured human epithelial cells. Moreover, the levels of phosphatidylinositol 3-kinase (PI3K) and pAkt were reduced in the epithelial cells and CTRP9 overexpression activated the PI3K/Akt pathway. CTRP9 could inhibit cell apoptosis and eNOS expression reduction in the cells pretreated with the PI3K/Akt inhibitor LY294002 and resist LY294002-induced ET-1 and MMP-2 secretion. Finally, to verify the role of CTRP9 in the progression of PH in vivo, the pcDNA-CTRP9 expression vector or CTRP9 siRNA was intravenously injected into rats with PH. Pulmonary arterial pressures of the rats were notably reduced by the pcDNA-CTRP9 injection and elevated by the CTRP9 siRNA injection. In conclusion, CTRP9 ameliorated PH by attenuating inflammation and improving endothelial cell survival and function.

C1QTNF6 is overexpressed in gastric carcinoma and contributes to the proliferation and migration of gastric carcinoma cells

“…cTRP4 was demonstrated to protect against apoptosis induced by chemotherapeutics and thereby promote tumor cell survival (3). The present study was the first to report the anti-apoptotic effect of C1QTNF6 in GC AGS cells; the results are consistent with those of previous studies (28)(29)(30), which suggested that c1QTNF family proteins primarily perform cytoprotective and anti-apoptotic functions. In addition, the results of the present study may be applied to a C1QTNF6-knockout animal model to extend and confirm the results derived from a cell culture model.…”

“…A number of protein members are involved in the regulation of cell apoptosis. Administration of cTRP9 was demonstrated to attenuate cardiomyocyte apoptosis following acute myocardial infarction (26) or myocardial ischemia reperfusion (27), and to decrease the apoptotic rate of primary pulmonary artery epithelial cells due to pulmonary arterial hypertension (28). cTRP3 protected bone marrow derived mesenchymal stem cells from hypoxia-induced apoptosis through the phosphoinositide 3-kinase/protein kinase B signaling pathway (29).…”

C1q/TNF-Related Protein-9 Ameliorates Ox-LDL-Induced Endothelial Dysfunction via PGC-1α/AMPK-Mediated Antioxidant Enzyme Induction

“…Administration of CTRP9 attenuated cardiomyocyte apoptosis and myocardial remodeling in mice after acute myocardial infarction [25]. CTRP9 attenuates the apoptosis of primary pulmonary artery epithelial cells, which is essential for amelioration of pulmonary arterial hypertension [26]. In the presence of CTRP9, the cardiac infarction, and cardiomyocytes apoptosis are markedly reversed in myocardial ischemia reperfusion rats [27].…”

C1q/TNF‐related protein 9: A novel therapeutic target in ischemic stroke?

“…It shows that CTRP9 plays an important role in protection of epithelial function which can be embodied by eNOS, endothelin (ET) ‐1 and matrix metalloproteinase (MMP) ‐2 (Li, Geng, Wang, Cheng, & Xu, ). Interestingly, serum CTRP9 concentrations and CTRP9 mRNA expression levels both deceased in PH patients compared with the normal participants (Li et al, ).…”