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

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Fibrosis Research

Background:

• The role of p38 mitogen-activated protein kinase (MAPK) in right ventricular (RV) hypertrophy and failure remains incompletely understood.
• Existing research implicates p38 MAPK in various cardiovascular diseases, but its specific contribution to RV pathobiology is unclear.

Purpose of the Study:

• To investigate the role of p38 MAPK in the pathophysiology of pressure overload-induced RV hypertrophy and failure.
• To evaluate the therapeutic potential of p38 MAPK inhibition in RV disease models.

Main Methods:

• Utilized mouse models of RV hypertrophy/failure induced by hypoxia or pulmonary artery banding.
• Administered the p38 MAPK inhibitor PH797804 and employed small interfering RNA for gene depletion in isolated RV fibroblasts.
• Conducted echocardiography, invasive hemodynamics, immunohistochemistry, collagen assays, immunofluorescence, and Western blotting.

Main Results:

• Increased phosphorylated p38 MAPK expression was observed in hypertrophied/failed human and mouse RVs.
• PH797804 treatment improved RV function and reduced cardiac fibrosis in mice.
• Inhibition of p38 MAPK attenuated transforming growth factor-β (TGF-β)-induced collagen production, stress fiber formation, SMAD2/3 phosphorylation, and MRTF-A nuclear translocation in RV fibroblasts, preventing fibroblast transdifferentiation.

Conclusions:

• p38 MAPK inhibition significantly enhances RV function and mitigates RV fibrosis.
• Targeting p38 MAPK in RV cardiac fibroblasts attenuates key fibrotic signaling pathways, including MRTF-A and SMAD3.
• p38 MAPK signaling plays a critical role in distinct disease-causing mechanisms underlying RV hypertrophy and failure.