Abstract
Right ventricular (RV) remodeling is one of the essential pathological features in pulmonary arterial hypertension (PAH). RV hypertrophy or fibrosis are the leading causes of RV remodeling. Magnolol (6, 6′, 7, 12-tetramethoxy-2,2′-dimethyl-1-β-berbaman, C18H18O2) is a compound isolated from Magnolia Officinalis. It possesses multiple pharmacological activities, such as anti-oxidation and anti-inflammation. This study aims to evaluate the effects and underlying mechanisms of magnolol on RV remodeling in hypoxia-induced PAH. In vivo, male Sprague Dawley rats were exposed to 10% O2 for 4 weeks to establish an RV remodeling model, which showed hypertrophic and fibrotic features (increases of Fulton index, cellular size, hypertrophic and fibrotic marker expression), accompanied by an elevation in phosphorylation levels of JAK2 and STAT3; these changes were attenuated by treating with magnolol. In vitro, the cultured H9c2 cells or cardiac fibroblasts were exposed to 3% O2 for 48 h to induce hypertrophy or fibrosis, which showed hypertrophic (increases in cellular size as well as the expression of ANP and BNP) or fibrotic features (increases in the expression of collagen Ⅰ, collagen Ⅲ, and α-SMA). Administration of magnolol and TG-101348 or JSI-124 (both JAK2 selective inhibitors) could prevent myocardial hypertrophy and fibrosis, accompanied by the decrease in the phosphorylation level of JAK2 and STAT3. Based on these observations, we conclude that magnolol can attenuate RV hypertrophy and fibrosis in hypoxia-induced PAH rats through a mechanism involving inhibition of the JAK2/STAT3 signaling pathway. Magnolol may possess the potential clinical value for PAH therapy.
Highlights
Pulmonary arterial hypertension (PAH) is a malignant cardiopulmonary vascular disease characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, which eventually leads to right ventricular (RV) remodeling and even Right ventricular (RV) failure (VonkNoordegraaf et al, 2013; Zelt et al, 2019)
We found that the wall thickness of RV in the diastole and systole period was significantly increased in pulmonary arterial hypertension (PAH) rats (Figures 2A–D), accompanied by a decrease in the ratio of PAAT/PAET (Figure 2E); these phenomena were markedly attenuated by magnolol at both dosages (10 and 20 mg/kg)
By using HE and Wheat germ agglutinin (WGA) staining, we found that the wall thickness of the RV, the cross-sectional area, and perimeter of individual cardiomyocyte significantly increased in rats exposed to hypoxia for 4 weeks, accompanied by an increase in the mRNA expressions of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the RV tissue, confirmed the role of myocardial hypertrophy in RV remodeling in hypoxic PAH
Summary
Pulmonary arterial hypertension (PAH) is a malignant cardiopulmonary vascular disease characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, which eventually leads to right ventricular (RV) remodeling and even RV failure (VonkNoordegraaf et al, 2013; Zelt et al, 2019). Current clinical drug treatment strategies for RV failure aim to enhance RV contractility or reduce RV afterload (Cassady and Ramani, 2020). It cannot effectively reverse the process of RV remodeling and RV failure during PAH. Seeking drugs with the potential to target the RV remodeling during PAH is of great significance for delaying the progression of PAH and improving the survival rate of PAH patients
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
