Interferon-γ ablation exacerbates myocardial hypertrophy in diastolic heart failure

Garcia AG, Wilson RM, Heo J, Murthy NR, Baid S, Ouchi N, Sam F. Interferon-gamma ablation exacerbates myocardial hypertrophy in diastolic heart failure. Am J Physiol Heart Circ Physiol 303: H587-H596, 2012. First published June 22, 2012; doi:10.1152/ajpheart.00298.2012.-Diastolic heart failure (HF) accounts for up to 50% of all HF admissions, with hypertension being the major cause of diastolic HF. Hypertension is characterized by left ventricular (LV) hypertrophy (LVH). Proinflammatory cytokines are increased in LVH and hypertension, but it is unknown if they mediate the progression of hypertension-induced diastolic HF. We sought to determine if interferon-gamma (IFN gamma) plays a role in mediating the transition from hypertension-induced LVH to diastolic HF. Twelve-week old BALB/c (WT) and IFN gamma-deficient (IFN gamma KO) mice underwent either saline (n = 12) or aldosterone (n = 16) infusion, uninephrectomy, and fed 1% salt water for 4 wk. Tail-cuff blood pressure, echocardiography, and gene/protein analyses were performed. Isolated adult rat ventricular myocytes were treated with IFN gamma (250 U/ml) and/or aldosterone (1 mu M). Hypertension was less marked in IFN gamma KO-aldosterone mice than in WT-aldosterone mice (127 +/- 5 vs. 136 +/- 4 mmHg; P < 0.01), despite more LVH (LV/body wt ratio: 4.9 +/- 0.1 vs. 4.3 +/- 0.1 mg/g) and worse diastolic dysfunction (peak early-to-late mitral inflow velocity ratio: 3.1 +/- 0.1 vs. 2.8 +/- 0.1). LV ejection fraction was no different between IFN gamma KO-aldosterone vs. WT-aldosterone mice. LV end systolic dimensions were decreased significantly in IFN gamma KO-aldosterone vs. WT-aldosterone hearts (1.12 +/- 0.1 vs. 2.1 +/- 0.3 mm). Myocardial fibrosis and collagen expression were increased in both IFN gamma KO-aldosterone and WT-aldosterone hearts. Myocardial autophagy was greater in IFN gamma KO-aldosterone than WT-aldosterone mice. Conversely, tumor necrosis factor-alpha and interleukin-10 expressions were increased only in WT-aldosterone hearts. Recombinant IFN gamma attenuated cardiac hypertrophy in vivo and modulated aldosterone-induced hypertrophy and autophagy in cultured cardiomyocytes. Thus IFN gamma is a regulator of cardiac hypertrophy in diastolic HF and modulates cardiomyocyte size possibly by regulating autophagy. These findings suggest that IFN gamma may mediate adaptive downstream responses and challenge the concept that inflammatory cytokines mediate only adverse effects.