{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T06:44:25Z","timestamp":1779345865307,"version":"3.51.4"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2001,9,11]]},"abstract":"<jats:p><jats:bold><jats:italic><jats:bold><jats:italic>Background<\/jats:italic><\/jats:bold><\/jats:italic><\/jats:bold>Numerous pathological mediators of cardiac hypertrophy (eg, neurohormones, cytokines, and stretch) have been shown to activate p38 MAPK. The purpose of the present study was to examine p38 MAPK activation and the effects of its long-term inhibition in a model of hypertensive cardiac hypertrophy\/dysfunction and end-organ damage.<\/jats:p><jats:p><jats:bold><jats:italic><jats:bold><jats:italic>Methods and Results<\/jats:italic><\/jats:bold><\/jats:italic><\/jats:bold>In spontaneously hypertensive stroke-prone (SP) rats receiving a high-salt\/high-fat diet (SFD), myocardial p38 MAPK was activated persistently during the development of cardiac hypertrophy and inactivated during decompensation. Long-term oral treatment of SFD-SP rats with a selective p38 MAPK inhibitor (SB239063) significantly enhanced survival over an 18-week period compared with the untreated group (100% versus 50%). Periodic echocardiographic analysis revealed a significant reduction in LV hypertrophy and dysfunction in the SB239063-treatment groups. Little or no difference in blood pressure was noted in the treatment or vehicle groups. Basal and stimulated (lipopolysaccharide) plasma tumor necrosis factor-\u03b1 concentrations were reduced in the SB239063-treatment groups. In vitro vasoreactivity studies demonstrated a significant preservation of endothelium-dependent relaxation in animals treated with the p38 MAPK inhibitor without effects on contraction or NO-mediated vasorelaxation. Proteinuria and the incidence of stroke (53% versus 7%) were also reduced significantly in the SB239063\u2013treated groups.<\/jats:p><jats:p><jats:bold><jats:italic><jats:bold><jats:italic>Conclusions<\/jats:italic><\/jats:bold><\/jats:italic><\/jats:bold>These results demonstrate a crucial role for p38 MAPK in hypertensive cardiac hypertrophy and end-organ damage. Interrupting its function with a specific p38 MAPK inhibitor halts clinical deterioration.<\/jats:p>","DOI":"10.1161\/hc3601.094275","type":"journal-article","created":{"date-parts":[[2007,9,28]],"date-time":"2007-09-28T18:31:09Z","timestamp":1191004269000},"page":"1292-1298","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":90,"title":["Hypertensive End-Organ Damage and Premature Mortality Are p38 Mitogen-Activated Protein Kinase\u2013Dependent in a Rat Model of Cardiac Hypertrophy and Dysfunction"],"prefix":"10.1161","volume":"104","author":[{"given":"Thomas M.","family":"Behr","sequence":"first","affiliation":[{"name":"From Cardiovascular Pharmacology, GlaxoSmithKline, King of Prussia, Pa, and the Department of Cardiology, St Luke\u2019s Hospital, New York, NY (J.D.S.-B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandhya S.","family":"Nerurkar","sequence":"additional","affiliation":[{"name":"From Cardiovascular Pharmacology, GlaxoSmithKline, King of Prussia, Pa, and the Department of Cardiology, St Luke\u2019s Hospital, New York, NY (J.D.S.-B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allen H.","family":"Nelson","sequence":"additional","affiliation":[{"name":"From Cardiovascular Pharmacology, GlaxoSmithKline, King of Prussia, Pa, and the Department of Cardiology, St Luke\u2019s Hospital, New York, NY (J.D.S.-B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert W.","family":"Coatney","sequence":"additional","affiliation":[{"name":"From Cardiovascular Pharmacology, GlaxoSmithKline, King of Prussia, Pa, and the Department of Cardiology, St Luke\u2019s Hospital, New York, NY (J.D.S.-B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tina N.","family":"Woods","sequence":"additional","affiliation":[{"name":"From Cardiovascular Pharmacology, GlaxoSmithKline, King of Prussia, Pa, and the Department of Cardiology, St 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