Abstract 5082: Interferon-γ Plays a Pivotal Role in Hypertension-Induced Cardiac Remodeling and Diastolic Heart Failure
Background: Diastolic heart failure (DHF) is clinical conundrum and accounts for ~50% of all HF admissions. There remains a paucity of therapies. Hypertension is the major cause of DHF and is associated with LV hypertrophy (LVH). Inflammatory cytokines are increased in hypertension but it is unknown if they mediate hypertension-induced cardiac remodeling. We tested the hypothesis that interferon-γ plays a pivotal role in the progression from hypertension-induced LVH to DHF.
Methods: Twelve-week old BALB/c (WT) and interferon-γ deficient (IFNγKO) mice underwent either saline (saline; n=10) or aldosterone-infusion (ALDO; n=20). All underwent uninephrectomy and drank 1% salt water for 4-weeks. Four-weeks after surgery, tail-cuff blood pressure (BP), echocardiogram and gene/protein analyses were performed. Isolated adult rat ventricular myocytes (ARVM) were treated with either interferon-γ (500nM) and/or aldosterone (50nM) for 30min.
Results: BP was increased in WT-ALDO vs. WT-saline mice (P<0.01). Interestingly BP was not as increased in IFNγKO-ALDO vs. WT-ALDO mice (127±5 vs. 136±4mmHg, P=NS). There was LVH in WT-ALDO vs. WT-saline mice (P<0.05). LVH was further increased in IFNγKO-ALDO vs. WT-ALDO mice (HW/BW ratio: 4.9±0.1 vs. 4.3±0.1mg/g; P<0.01). LV end diastolic dimension was no different between IFNã KO-ALDO vs. WT-ALDO hearts. However, LV end systolic dimension (LVESD) was significantly smaller in IFNã KO-ALDO vs. IFNã KO-saline and WT-ALDO mice (1.12±0.1 vs. 1.4±0.1, and 2.1±0.3, respectively; P <0.05 for both). LVH was associated with an increase in myocardial ANP gene and protein expression in WT-ALDO hearts (P<0.05 vs. WT-sham). Intriguingly ANP gene and protein expression was not increased in IFNã KO-ALDO vs. WT-ALDO hearts. In ARVM pretreatment with interferon-ã prior to aldosterone significantly inhibited aldosterone-induced ERK1/2 phosphorylation, another marker of cardiomyocyte hypertrophy (P<0.05).
Conclusions: Interferon-γ modulates cardiomyocyte hypertrophy partly independently of BP. There is a propensity to adverse cardiac remodeling with interferon-γ deficiency in this model of hypertension and DHF. Our findings suggest that interferon-γ may represent a novel target for hypertensive heart disease and DHF.