Interferon-γ ablation exacerbates myocardial hypertrophy in diastolic heart failure

Abstract

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-γ (IFNγ) plays a role in mediating the transition from hypertension-induced LVH to diastolic HF. Twelve-week old BALB/c (WT) and IFNγ-deficient (IFNγKO) 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 IFNγ (250 U/ml) and/or aldosterone (1 μM). Hypertension was less marked in IFNγKO-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 IFNγKO-aldosterone vs. WT-aldosterone mice. LV end systolic dimensions were decreased significantly in IFNγKO-aldosterone vs. WT-aldosterone hearts (1.12 ± 0.1 vs. 2.1 ± 0.3 mm). Myocardial fibrosis and collagen expression were increased in both IFNγKO-aldosterone and WT-aldosterone hearts. Myocardial autophagy was greater in IFNγKO-aldosterone than WT-aldosterone mice. Conversely, tumor necrosis factor-α and interleukin-10 expressions were increased only in WT-aldosterone hearts. Recombinant IFNγ attenuated cardiac hypertrophy in vivo and modulated aldosterone-induced hypertrophy and autophagy in cultured cardiomyocytes. Thus IFNγ is a regulator of cardiac hypertrophy in diastolic HF and modulates cardiomyocyte size possibly by regulating autophagy. These findings suggest that IFNγ may mediate adaptive downstream responses and challenge the concept that inflammatory cytokines mediate only adverse effects.

Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation

“…We found that IFN-γ deficiency resulted in blunted hypertension in response to Ang II infusion ( Figure 9). Our findings are in agreement with a study by Garcia et al (20) in which IFN-γ deficiency protected against hypertension in a mouse model of uninephrectomy when combined with aldosterone infusion and salt feeding.…”

CD70 Exacerbates Blood Pressure Elevation and Renal Damage in Response to Repeated Hypertensive Stimuli

“…We found that this form of hypertension is associated with the accumulation of memory T cells in the kidney and bone marrow and that these cells are major sources of IL-17A and IFN-γ, which we and others have shown to be important in mediating hypertension and its end-organ damage. 3, 20, 21 The formation of memory T cells in hypertension was dependent on CD70, and we found that mice lacking this co-stimulatory ligand, or lacking IFN-γ did not demonstrate salt-induced hypertension following L-NAME exposure. To confirm these findings we employed a second model in which we initially exposed mice to a two week infusion of a pressor dose of ang II (490 ng/kg/min).…”

Effects of Adiponectin on Calcium-Handling Proteins in Heart Failure With Preserved Ejection Fraction

“…Pro-inflammatory cytokines, such as TNF-α which is pro-hypertrophic 47 , are increased in diastolic dysfunction and HFpEF 18 (Supplemental Figure 2). We recently showed that IFN-γ, a pro-inflammatory cytokine attenuated cardiac hypertrophy and is a regulator of cardiac hypertrophy in HFpEF thus disputing the notion that inflammatory cytokines mediate only adverse effects 48 .…”