biostudies-literatureSedighi SNHLBI NIH HHS36082-36097https://www.ebi.ac.uk/biostudies/studies/S-EPMC12371761biostudies-literatureUnknown10(32)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 Ca²⁺-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.ACS omegaInhibition of Cardiac p38 Highlights the Role of the Phosphoproteome in Heart Failure Progression.PMC12371761R01 HL134821R01 HL164478O'Rourke BSedighi SO'Meally RLiu TCole RNFoster DBfalseInhibition of Cardiac p38 Highlights the Role of the Phosphoproteome in Heart Failure Progression.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 Ca²⁺-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.2025-01-01T00:00:00Z2025 Aug2026-06-01T13:52:36.587Z2026-04-08T13:05:35.333ZS-EPMC123717614086071510.1021/acsomega.5c03687