p38 MAPK Inhibition Improves Heart Function in Pressure-Loaded Right Ventricular Hypertrophy

Abstract

Although p38 mitogen-activated protein kinase (MAPK) is known to have a role in ischemic heart disease and many other diseases, its contribution to the pathobiology of right ventricular (RV) hypertrophy and failure is unclear. Therefore, we sought to investigate the role of p38 MAPK in the pathophysiology of pressure overload-induced RV hypertrophy and failure. The effects of the p38 MAPK inhibitor PH797804 were investigated in mice with RV hypertrophy/failure caused by exposure to hypoxia or pulmonary artery banding. In addition, the effects of p38 MAPK inhibition or depletion (by small interfering RNA) were studied in isolated mouse RV fibroblasts. Echocardiography, invasive hemodynamic measurements, immunohistochemistry, collagen assays, immunofluorescence staining, and Western blotting were performed. Expression of phosphorylated p38 MAPK was markedly increased in mouse and human hypertrophied/failed RVs. In mice, PH797804 improved RV function and inhibited cardiac fibrosis compared with placebo. In isolated RV fibroblasts, p38 MAPK inhibition reduced transforming growth factor (TGF)-β-induced collagen production as well as stress fiber formation. Moreover, p38 MAPK inhibition/depletion suppressed TGF-β-induced SMAD2/3 phosphorylation and myocardin-related transcription factor A (MRTF-A) nuclear translocation, and prevented TGF-β-induced cardiac fibroblast transdifferentiation. Moreover, p38 MAPK inhibition in mice exposed to pulmonary artery banding led to diminished nuclear levels of MRTF-A and phosphorylated SMAD3 in RV fibroblasts. Together, our data indicate that p38 MAPK inhibition significantly improves RV function and inhibits RV fibrosis. Inhibition of p38 MAPK in RV cardiac fibroblasts, resulting in coordinated attenuation of MRTF-A cytoplasmic-nuclear translocation and SMAD3 deactivation, indicates that p38 MAPK signaling contributes to distinct disease-causing mechanisms.

Oxidative Stress, Kinase Activity and Inflammatory Implications in Right Ventricular Hypertrophy and Heart Failure under Hypobaric Hypoxia

“…Supporting the role of fibrosis, a recent study in rats with RVH induced by hypobaric hypoxia (4500 m) exposure showed a fibrotic process in the RV [89]. A study in mice under other types of hypoxia (chronic normobaric hypoxia, 10% O 2 ) showed that animals with PO-induced RVH and HF exhibited increased p38α expression, which was related to several effects, such as increased collagen and smooth muscle actin α (α-SMA) content leading to fibrosis [90]. Additionally, it is important to highlight that p38α is necessary for the differentiation of cardiac fibroblasts to myofibroblasts through the nuclear translocation of myocardin-related transcription factor A (MRTF-A) [90].…”

“…A study in mice under other types of hypoxia (chronic normobaric hypoxia, 10% O 2 ) showed that animals with PO-induced RVH and HF exhibited increased p38α expression, which was related to several effects, such as increased collagen and smooth muscle actin α (α-SMA) content leading to fibrosis [90]. Additionally, it is important to highlight that p38α is necessary for the differentiation of cardiac fibroblasts to myofibroblasts through the nuclear translocation of myocardin-related transcription factor A (MRTF-A) [90]. However, there are other molecules induced by hypoxia, such as IL-6, endothelin-1 (ET-1) and transforming growth factor α and β (TGF-α and TGF-β), that are related to the transdifferentiation of fibroblasts to myofibroblasts [91], highlighting the key role of IL-6 [92], as will be discussed later.…”

miRNA-PDGFRB/HIF1A-lncRNA CTEPHA1 Network Plays Important Roles in the Mechanism of Chronic Thromboembolic Pulmonary Hypertension

“…Numerous studies have reported that MAPK plays an important role in the development of PH. [22][23][24][25] CTEPH is a special type of PH, and if MAPK plays the same role in CTEPH, further analysis and verification need to be done in the future. Secondly, in our miRNA-gene network, miRNA-149 is at the core position (Degree = 58).…”

Multiple Levels of PGC-1α Dysregulation in Heart Failure

“…The expression and activation of p38 MAPK transiently increase in the mouse heart during pressure overload (2 and 4 weeks of TAC) (137). The inhibition of p38 MAPK is beneficial in a mouse model of right ventricular hypertrophy and failure that was induced by pulmonary artery banding (138). It remains elusive whether phosphorylation of PGC-1α via p38 MAPK plays a role in metabolic remodeling in response to hemodynamic stress.…”