No abstract

Rationale: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with aberrant pulmonary artery smooth muscle cells (PASMCs) proliferation, endothelial dysfunction, and extracellular matrix remodeling. Objective: Right ventricular (RV) failure is an important prognostic factor in PAH. Thus, we need to elucidate a novel therapeutic target in both PAH and RV failure. Methods and Results: We performed microarray analysis in PASMCs from patients with PAH (PAH-PASMCs) and controls. We found a ADAMTS8 (disintegrin and metalloproteinase with thrombospondin motifs 8), a secreted protein specifically expressed in the lung and the heart, was upregulated in PAH-PASMCs and the lung in hypoxia-induced pulmonary hypertension (PH) in mice. To elucidate the role of ADAMTS8 in PH, we used vascular smooth muscle cell-specific ADAMTS8-knockout mice (ADAMTS ΔSM22 ). Hypoxia-induced PH was attenuated in ADAMTS ΔSM22 mice compared with controls. ADAMTS8 overexpression increased PASMC proliferation with downregulation of AMPK (AMP-activated protein kinase). In contrast, deletion of ADAMTS8 reduced PASMC proliferation with AMPK upregulation. Moreover, deletion of ADAMTS8 reduced mitochondrial fragmentation under hypoxia in vivo and in vitro. Indeed, PASMCs harvested from ADAMTS ΔSM22 mice demonstrated that phosphorylated DRP-1 (dynamin-related protein 1) at Ser637 was significantly upregulated with higher expression of profusion genes (Mfn1 and Mfn2) and improved mitochondrial function. Moreover, recombinant ADAMTS8 induced endothelial dysfunction and matrix metalloproteinase activation in an autocrine/paracrine manner. Next, to elucidate the role of ADAMTS8 in RV function, we developed a cardiomyocyte-specific ADAMTS8 knockout mice (ADAMTS8 ΔαMHC ). ADAMTS8 ΔαMHC mice showed ameliorated RV failure in response to chronic hypoxia. In addition, ADAMTS8 ΔαMHC mice showed enhanced angiogenesis and reduced RV ischemia and fibrosis. Finally, high-throughput screening revealed that mebendazole, which is used for treatment of parasite infections, reduced ADAMTS8 expression and cell proliferation in PAH-PASMCs and ameliorated PH and RV failure in PH rodent models. Conclusions: These results indicate that ADAMTS8 is a novel therapeutic target in PAH.

Although postcapillary pulmonary hypertension (PH) is an important prognostic factor for patients with heart failure (HF), its pathogenesis remains to be fully elucidated. To elucidate the different roles of Rho-kinase isoforms, ROCK1 and ROCK2, in cardiomyocytes in response to chronic pressure overload, we performed transverse aortic constriction (TAC) in cardiac-specific ROCK1-deficient () and ROCK2-deficient () mice. Cardiomyocyte-specific ROCK1 deficiency promoted pressure-overload-induced cardiac dysfunction and postcapillary PH, whereas cardiomyocyte-specific ROCK2 deficiency showed opposite results. Histological analysis showed that pressure-overload-induced cardiac hypertrophy and fibrosis were enhanced in mice compared with controls, whereas cardiac hypertrophy was attenuated in mice after TAC. Consistently, the levels of oxidative stress were up-regulated in hearts and down-regulated in hearts compared with controls after TAC. Furthermore, cyclophilin A (CyPA) and basigin (Bsg), both of which augment oxidative stress, enhanced cardiac dysfunction and postcapillary PH in mice, whereas their expressions were significantly lower in mice. In clinical studies, plasma levels of CyPA were significantly increased in HF patients and were higher in patients with postcapillary PH compared with those without it. Finally, high-throughput screening demonstrated that celastrol, an antioxidant and antiinflammatory agent, reduced the expressions of CyPA and Bsg in the heart and the lung, ameliorating cardiac dysfunction and postcapillary PH induced by TAC. Thus, by differentially affecting CyPA and Bsg expressions, ROCK1 protects and ROCK2 jeopardizes the heart from pressure-overload HF with postcapillary PH, for which celastrol may be a promising agent.

The results indicate that plasma CyPA levels can be used to predict all-cause death, rehospitalization, and coronary revascularization in patients with coronary artery disease and that when combined with other biomarkers (hsCRP and brain natriuretic peptide levels), the CyPA levels have further enhanced prognostic impacts in those patients.

BackgroundCirculating proteins are exposed to vascular endothelial layer and influence their functions. Among them, adipsin is a member of the trypsin family of peptidases and is mainly secreted from adipocytes, monocytes, and macrophages, catalyzing the rate‐limiting step of the alternative complement pathway. However, its pathophysiological role in cardiovascular disease remains to be elucidated. Here, we examined whether serum adipsin levels have a prognostic impact in patients with coronary artery disease.Methods and ResultsIn 370 consecutive patients undergoing diagnostic coronary angiography, we performed a cytokine array analysis for screening serum levels of 50 cytokines/chemokines and growth factors. Among them, classification and regression analysis identified adipsin as the best biomarker for prediction of their long‐term prognosis (median 71 months; interquartile range, 55–81 months). Kaplan–Meier curve showed that higher adipsin levels (≥400 ng/mL) were significantly associated with all‐cause death (hazard ratio [HR], 4.2; 95% CI, 1.7–10.6 [P<0.001]) and rehospitalization (HR, 2.4; 95% CI, 1.7–3.5 [P<0.001]). Interestingly, higher high‐sensitivity C‐reactive protein levels (≥1 mg/L) were significantly correlated with all‐cause death (HR, 3.2; 95% CI, 1.7–5.9 [P<0.001]) and rehospitalization (HR, 1.5, 95% CI, 1.1–1.9 [P<0.01]). Importantly, the combination of adipsin (≥400 ng/mL) and high‐sensitivity C‐reactive protein (≥1 mg/L) was more significantly associated with all‐cause death (HR, 21.0; 95% CI, 2.9–154.1 [P<0.001]). Finally, the receiver operating characteristic curve demonstrated that serum adipsin levels predict the death caused by acute myocardial infarction in patients with coronary artery disease (C‐statistic, 0.847).ConclusionsThese results indicate that adipsin is a novel biomarker that predicts all‐cause death and rehospitalization in patients with coronary artery disease, demonstrating the novel aspects of the alternative complementary system in the pathogenesis of coronary artery disease.