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(Circulation. 2001;104:1292.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Hypertensive End-Organ Damage and Premature Mortality Are p38 Mitogen-Activated Protein Kinase–Dependent in a Rat Model of Cardiac Hypertrophy and Dysfunction

Thomas M. Behr, MD^*; Sandhya S. Nerurkar, MS^*; Allen H. Nelson, BS; Robert W. Coatney, DVM; Tina N. Woods, MS; Anthony Sulpizio, BS; Sudeep Chandra, PhD; David P. Brooks, PhD; Sanjay Kumar, PhD; John C. Lee, PhD; Eliot H. Ohlstein, PhD; Christiane E. Angermann, MD; Jerry L. Adams, PhD; Joseph Sisko, PhD; Jonathan D. Sackner-Bernstein, MD; Robert N. Willette, PhD

From Cardiovascular Pharmacology, GlaxoSmithKline, King of Prussia, Pa, and the Department of Cardiology, St Luke’s Hospital, New York, NY (J.D.S.-B.).

Correspondence to Robert N. Willette, PhD, Department of Cardiovascular Pharmacology, UW2510, GlaxoSmithKline, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406. E-mail robert_n_willette{at}gsk.com

Background— 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.

Methods and Results— 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- 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–treated groups.

Conclusions— 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.

Key Words: heart failure • hypertension • signal transduction • stroke • hypertrophy

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