Abstract
Heart failure (HF) is a complex condition. Among altered signal transduction pathways associated with HF pathogenesis, the stress-activated p38 mitogen-activated protein kinase (Mapk) pathway has attracted attention for its role in HF progression and cardiac hypertrophy. However, the mechanisms by which p38-Mapk influences HF remain unclear. Addressing knowledge gaps may provide insight into why p38 inhibition has yielded inconsistent outcomes in clinical trials. Here, we investigate the effects of p38-Mapk inhibition via SB203580 on cardiac remodeling in a guinea pig model of HF and sudden cardiac death. Using an HF model with ascending aortic constriction and daily isoproterenol (ACi) administration, we assessed three groups: sham-operated controls, untreated ACi, and ACi treated with SB203580 (ACiSB). Cardiac function was evaluated by M-mode echocardiography. Proteome and phosphoproteome profiles were analyzed using multiplexed Tandem Mass Tag labeling and LC-MS/MS. Our findings demonstrate that SB203580 treatment protects against cardiac dysfunction in HF. Proteomic data indicate that SB203580 exerts broad protection of the cardiac phosphoproteome, inhibiting maladaptive p38-dependent phosphorylation, extending to Pka and Ampk networks, ultimately protecting the phosphorylation status of critical myofibrillar and Ca(2+)-handling proteins. Though SB203580 had a limited impact on widespread protein changes in HF, its biosignature revealed preserved mitochondrial energetics and reduced oxidative and inflammatory stress.