Systemic Immunosuppression Fails to Suppress Cardiac Cytokine Induction in Pressure Overload Hypertrophy in Rats

Abstract

Activation of cytokines such as interleukin-6 (IL-6) has been implicated in the pathogenesis of left ventricular dysfunction and hypertrophy since they have been shown to mediate cell proliferation, negative inotropic effects and myocardial hypertrophy. However, the effects of immunosuppressive therapy on cytokines in the treatment of heart failure and hypertrophy are unclear. To test the hypothesis that systemic immunosuppresion may influence serum and myocardial IL-6 and, thereby, may affect progression of myocardial hypertrophy. We studied the effects of chronic treatment with methotrexate (MTx) and with the ACE inhibitor ramipril on IL-6 in rats with pressure overload left ventricular hypertrophy (LVH) due to aortic banding. Animals were treated with either vehicle (n = 6) or methotrexate (MTx 1: 0.3 mg/kg BW/week; MTx 2: 0.9 mg/kg BW/week; i.p.; n = 6 each group) once a week during weeks 4-12 after aortic banding; sham-operated rats served as controls (CTRL; n = 8). During the development of LVH, serum IL-6 was determined by rat-specific ELISA and 12 weeks after aortic banding myocardial IL-6 was measured using a tissue superfusion technique or determining of protein concentration. Aortic banding significantly lowered blood pressure, increased left ventricular weight and resulted in elevated serum IL-6 levels (27.6 +/- 5.1 vs 19.1 +/- 2.3 pg/ml, p < 0.05) compared to CTRL. MTx treatment normalised the initially elevated serum IL-6 levels after 8 weeks of treatment. The significant increase in IL-6 concentration in the superfusate of all aortic banding groups compared to CTRL (< 30%, p < 0.05) was not altered by prior MTx therapy. Accordingly, both doses of MTx failed to prevent LVH progression (1.67 +/- 0.23 g vs. 2.32 +/- 0.31 g, p < 0.05). In contrast, chronic inhibition of the RAAS not only prevents LVH but also reduces myocardial IL-6 concentration (6898 +/- 355 vs. 3073 +/- 366 pg/mg protein, p < 0.05). Pressure overload LVH in rats is characterized by an increase in serum levels of IL-6 as well as myocardial IL-6. Chronic immunosuppressive therapy normalized systemic IL-6 levels, but failed to reduce cardiac IL-6 expression and the progression of LVH, while ACE inhibition is sufficient to modify LVH and thereby normalises myocardial IL-6 expression.