Deletion Of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy And Dysfunction

Objective:To demonstrate the role of genetic deletion of interleukin-6 (IL-6) during myocardial hypertrophy and also elucidate the underlying mechanism.Methods and Results:Adult IL-6 knock out (IL-6 KO) and wild-type (WT) mice underwent either sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiography over 6 weeks and invasive hemodynamic studies after 6 weeks showed preserved cardiac function and reduced cardiac hypertrophy in IL-6 KO mice compared to WT in the TAC group. Histological studies performed at various time points following the surgery showed lower fibrosis and apoptosis in IL-6 KO mice compared to WT in the TAC group. The above-mentioned parameters were not significantly different in the sham group. Transcriptional profiling and protein characterization using the samples isolated from harvested tissue identified Ca2+/calmodulin-dependent protein (CaMKII) and signal transducer and activator of transcription 3 (STAT3) activation as an important underlying mechanism during cardiac hypertrophy induced by TAC. Similar results were noted when isolated cardiomyocytes from WT and IL-6 KO mice were exposed to various pro-hypertrophy agents. We also observed that overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation. Treatment of H9c2 cells with recombinant IL-6 induced STAT3 activation that was attenuated by CaMKII inhibition. Overall, these results highlight the important contribution of CaMKII dependent activation of STAT3 during cardiomyocyte hypertrophy.Conclusions:Genetic deletion of IL-6 attenuated adverse cardiac remodeling and dysfunction induced by pressure overload. CaMK? is involved in IL-6-induced myocardial hypertrophy and contributes to IL-6 induced STAT3 activation. These data suggest a possible therapeutic potential of IL-6 inhibition to ameliorate cardiac hypertrophy and dysfunction in patients with systemic hypertension.