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

Abstract

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. (Circulation. 2001;

Interfering with MAP Kinase Docking Interactions: Implications and Perspectives for the p38 Route

“…21 p38 inhibition prevents failure-induced cardiac damage caused by fibrosis and apoptosis, [21][22][23] and also tissue damage in other organs. 24,25 Similar results are obtained by genetic ablation of the p38 route (reviewed in ref. 17) while genetic activation in mice of the p38 pathway causes elevated cardiac dysfunction 26 and early death.…”

p38 MAPK Inhibitors Ameliorate Target Organ Damage in Hypertension: Part 1. p38 MAPK-Dependent Endothelial Dysfunction and Hypertension

“…The introduction of the SFD induces a progressive increase in blood pressure in the SHR-SP within 2 weeks with concomitant depression of endothelial-dependent vasorelaxation, which is followed by evidence of renal dysfunction (albuminuria) and subsequent neurological deficits (Behr et al, 2001;Ma et al, 2001). Thus, it seems that endothelial dysfunction (loss of bioavailable endothelial NO) contributes to the progression and maintenance of chronic hypertension and is a likely determinant of the prothrombotic state and target organ damage observed in this model (Behr et al, 2001;Ma et al, 2001;Yamashita et al, 2002).…”

“…SFD-SHR-SPs have an accelerated mortality rate and were promptly euthanized when signs of morbidity were noted. These signs may include piloerection, lack of grooming, hypersensitivity to sound or touch, loss of appetite in the setting of cachexia, ataxia, decreased movement, and convulsive movements (Behr et al, 2001).…”

Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis-induced myocardial dysfunction

“…In another study, the activation of p38-MAPK was demonstrated to induce a negative inotropic effect in ARVM by decreasing the response of myofilaments to Ca 2+ during the onset of heart failure (Liao et al, 2002). In addition, during hypertensive endorgan damage, p38-MAPK phosphorylation was found to be related to premature mortality in a rat model of heart failure (Behr et al, 2001). Our laboratory demonstrated that bigET-1 upregulated p38-MAPK, but not ERK phosphorylation, in septic adult rat ventricular myocytes.…”