Inhibition of Cardiac p38 Highlights the Role of the Phosphoproteome in Heart Failure Progression

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Signal Transduction

Background:

• Heart failure (HF) involves complex signaling pathway alterations.
• The stress-activated p38 mitogen-activated protein kinase (MAPK) pathway is implicated in HF pathogenesis and cardiac hypertrophy.
• Understanding p38-MAPK mechanisms is crucial for clarifying inconsistent clinical trial outcomes of p38 inhibition.

Purpose of the Study:

• To investigate the effects of p38-MAPK inhibition using SB203580 on cardiac remodeling in a guinea pig model of HF.
• To elucidate the molecular mechanisms underlying p38-MAPK's role in HF progression.

Main Methods:

• Established a guinea pig model of HF via ascending aortic constriction and isoproterenol administration (ACi).
• Assessed cardiac function using M-mode echocardiography.
• Analyzed cardiac proteome and phosphoproteome profiles using multiplexed Tandem Mass Tag labeling and LC-MS/MS.

Main Results:

• SB203580 treatment significantly protected against cardiac dysfunction in the HF model.
• Proteomic analysis revealed SB203580 broadly protected the cardiac phosphoproteome, inhibiting p38-MAPK-dependent phosphorylation and impacting Pka and Ampk networks.
• SB203580 preserved the phosphorylation status of key myofibrillar and Ca2+ handling proteins, maintained mitochondrial energetics, and reduced oxidative and inflammatory stress.

Conclusions:

• p38-MAPK inhibition via SB203580 offers cardioprotection in HF by preserving phosphoproteome integrity and mitigating stress.
• SB203580's protective effects extend beyond direct p38-MAPK targets to influence broader cellular energetics and stress responses.
• Targeting the p38-MAPK pathway holds therapeutic potential for HF, warranting further investigation into its complex downstream effects.