Eprosartan improves cardiac performance, reduces cardiac hypertrophy and mortality and downregulates myocardial monocyte chemoattractant protein-1 and inflammation in hypertensive heart disease.

OBJECTIVE: The purpose of this investigation was to determine whether angiotensin II receptor (AII1R) antagonism interferes with cardiac monocyte chemoattractant protein-1 (MCP-1) expression in hypertrophic cardiomyopathy and failure. DESIGN: We studied the effects of the AII1R antagonist eprosartan on MCP-1 expression, and on the recruitment of macrophages into the myocardium in a model of cardiac hypertrophy and morbidity/mortality. METHODS: Stroke-prone spontaneously hypertensive rats fed a high-salt, high-fat diet (SFD) developed heart failure characterized by left ventricular (LV) hypertrophy/pathology and hypocontractility. These rats received either normal diet, SFD, or SFD with the daily administration of 30 mg/kg eprosartan for 28 weeks. LV function and wall thickness was assessed by echocardiography, MCP-1 expression was measured by TaqMan real-time polymerase chain reaction, enzyme-linked immunosorbent assay and immunohistochemistry, and macrophage infiltration into the LV was determined by microscopy. RESULTS: Eprosartan reduced the rate of morbidity/mortality (P = 0.001), LV MCP-1 mRNA (P < 0.05) and protein expression (P < 0.01), and LV macrophage infiltration (P < 0.01), while preserving ventricular function (P < 0.05). Eprosartan also produced a moderate (16%; P < 0.05) decrease in blood pressure. CONCLUSIONS: These data demonstrate that AII1R antagonism in an animal model of hypertensive heart disease reduces MCP-1 expression in the myocardium that results in reduced macrophage recruitment. These effects parallel the preservation of LV systolic function and the reduction in cardiac remodeling/disease progression and reduced morbidity/mortality. Suppression of MCP-1 expression might explain in part the beneficial effects of AII1R antagonism in this model.

p38 mitogen-activated protein kinase inhibitors for the treatment of chronic cardiovascular disease.

p38 Mitogen-activated protein kinase (MAPK) has been implicated in cardiovascular disease and is activated by various factors, including neurohormones (e.g., catecholamines, angiotensin II and endothelin), hypoxia and wall stress. Activation of p38 MAPK can cause cardiac hypertrophy, negative inotropy and endothelial dysfunction. All of these conditions lead to chronic cardiovascular disease, which is becoming an ever growing burden on society. p38 MAPK inhibition may therefore be an interesting therapeutic approach to the treatment of various cardiovascular diseases. However, in vitro and in vivo results are conflicting and caution must be applied in the translation of bench results to the clinic.