Wnt5a attenuates hypoxia-induced pulmonary arteriolar remodeling and right ventricular hypertrophy in mice

Hypoxic pulmonary hypertension (HPH), which is characterized by pulmonary arteriolar remodeling and right ventricular hypertrophy, is still a life-threatening disease with the current treatment strategies. The underlying molecular mechanisms of HPH remain unclear. Our previously published study showed that Wnt5a, one of the ligands in the Wnt family, was critically involved in the inhibition of hypoxia-induced pulmonary arterial smooth muscle cell proliferation by downregulation of β-catenin/cyclin D1 in vitro. In this study, we investigated the possible functions and mechanisms of Wnt5a in HPH in vivo. Recombinant mouse Wnt5a (rmWnt5a) or phosphate buffered saline (PBS) was administered to male C57/BL6 mice weekly from the first day to the end of the two or four weeks after exposed to hypoxia (10% O₂). Hypoxia-induced pulmonary hypertension was associated with a marked increase in β-catenin/cyclin D1 expression in lungs. Right ventricular systolic pressure and right ventricular hypertrophy index were reduced in animals treated with rmWnt5a compared with PBS. Histology showed less pulmonary vascular remodeling and right ventricular hypertrophy in the group treated with rmWnt5a than with PBS. Treatment with rmWnt5a resulted in a concomitant reduction in β-catenin/cyclin D1 levels in lungs. These data demonstrate that Wnt5a exerts its beneficial effects on HPH by regulating pulmonary vascular remodeling and right ventricular hypertrophy in a manner that is associated with reduction in β-catenin/cyclin D1 signaling. A therapy targeting the β-catenin/cyclin D1 signaling pathway might be a potential strategy for HPH treatment.     

Plasma myostatin levels are related to the extent of right ventricular dysfunction in exacerbation of chronic obstructive pulmonary disease

Objective: To investigate the relationship between plasma myostatin levels and right ventricle (RV) dysfunction (RVD) in acute exacerbation of chronic obstructive pulmonary disease (AECOPD).

Methods: The study recruited 84 patients with AECOPD. Plasma myostatin was analyzed and tricuspid annular plane systolic excursion (TAPSE)?<?16?mm was used as the main indicator for RVD.

Results: Plasma myostatin levels were significantly higher in 47 patients with RVD than 37 ones without (P?<?0.005). Multivariate regression analysis revealed that myostatin levels correlated significantly with TAPSE values and RV myocardial performance index (p?<?0.001) among the study patients.

Conclusion: Plasma myostatin is a potential biomarker for improving diagnosis of RVD in AECOPD.     

SPARCL1 as a biomarker of maladaptive right ventricular remodelling in pulmonary hypertension

Abstract

Aim: This study assessed the utility of SPARC-like protein 1 (SPARCL1) as a biomarker of maladaptive right ventricular (RV) function in patients with pulmonary hypertension (PH).

Methods: In this prospective study, we examined SPARCL1 levels in 105 patients with adaptive (n?=?34) and maladaptive RV (n?=?32) pressure overload caused by PH, dilated cardiomyopathy (DCM, n?=?18) with LVEF < 35% and preserved RV function and controls without LV or RV abnormalities (n?=?21).

Results: The median SPARCL1 concentration in patients with maladaptive RV function was higher than in those with adaptive RV function (p?<?0.01), DCM (p?<?0.001) or controls (p?<?0.001). Patients with adaptive RV function had higher SPARCL1 concentrations than controls (p?<?0.05), whereas there was no difference between adaptive RV and DCM. SPARCL1 showed good predictive power for maladaptive RV (AUC 0.77, p?<?0.001) with an optimal cut-off value of 9.66?ng/ml. The TAPSE/PASP ratio was the only independent predictor of SPARCL1?≥?9.66?ng/ml in multivariable logistic regression analysis.

Conclusion: SPARCL1 shows potential as novel biomarker of RV pathological remodelling and is associated with RV maladaptation and ventriculoarterial uncoupling in PH.     

Expression of ApoA5 and its function in the right ventricular failing and remodeling secondary to pulmonary hypertension

Right heart failure and right ventricular (RV) remodeling were the main reason for mortality of pulmonary hypertension (PH) patients. Apolipoprotein AV (ApoA5) is a key regulator of plasma triglyceride and have multifunction in several target organs. We detected decreased ApoA5 in serum of patients with PH and both in serum and RV of monocrotaline‐induced PH model. Exogenously, overexpression ApoA5 by adenovirus showed protective effects on RV failure and RV fibrosis secondary to PH. In addition, in vitro experiments showed ApoA5 attenuated the activation of fibroblast induced by transforming growth factor β1 and synthesis and secretion of extracellular matrix by inhibiting focal adhesion kinase‐c‐Jun N‐terminal kinase‐Smad3 pathway. Finally, we suggest that ApoA5 may potentially be a pivotal target for RV failure and fibrosis secondary of PH.     

Genetic predisposition to left ventricular dysfunction: a multigenic and multi-analytical approach

Background

Left ventricular dysfunction (LVD) is a complex, multifactorial condition, caused by mechanical, neurohormonal, and genetic factors. We have previously observed association of renin–angiotensin–aldosterone system (RAAS), matrix metalloproteinases (MMPs) and inflammatory pathway genes with LVD. Therefore the present study was undertaken to identify the combination of genetic variants and their possible interactions contributing towards genetic susceptibility to LVD in the background of coronary artery disease (CAD).

Methods and results

The study included 230 healthy controls and 510 consecutive patients with angiographically confirmed CAD. Among them, 162 with reduced left ventricle ejection fraction (LVEF ≤ 45%) were categorized as having LVD. We analyzed 11 polymorphisms of RAAS, MMPs and inflammatory pathways. Single locus analysis showed that AT1 A1166C (p value < 0.001; OR = 3.67), MMP9 R668Q (p value = 0.007; OR = 3.48) and NFKB1-94 ATTG ins/del (p value = 0.013; OR = 2.01) polymorphisms were independently associated with LVD when compared with both non-LVD patients and healthy controls. High-order gene–gene interaction analysis, using classification and regression tree (CART) and multifactor dimensionality reduction (MDR) revealed that AT1 A1166C and NFKB1-94 ATTG ins/del polymorphisms jointly increased the risk of LVD to great extent (p-value = 0.001; OR = 8.55) and best four-factor interaction model consisted of AT1 A1166C, MMP7 A-181G, MMP9 R668Q and NFKB1-94 ATTG ins/del polymorphisms with testing accuracy of 0.566 and cross validation consistency (CVC) = 9/10 (permutation p < 0.001) showed increased risk for LVD respectively.

Conclusion

AT1 A1166C independently and in combination with MMP9 R668Q and NFKB1-94 ATTG ins/del polymorphisms plays important role in conferring genetic susceptibility to LVD in CAD patients.