Ventricular dysfunction after pressure overload is associated to impaired CD4 CD8 recruitment in diabetic mice

Abstract

Cardiac hypertrophy and diabetes mellitus (DM) are independent risk factors for the development of heart failure. We induced left ventricular (LV) pressure overload by transverse aortic constriction (TAC) in wild-type mice (WT) and in mice homozygous for a mutation in leptin receptor (db/db) showing type II DM phenotype. Seven days after TAC WT but not db/db mice showed a significant increase in LV mass calculated by LV weight to body weight (BW) ratio despite a similar pressure gradient (51.7 mm Hg in WT vs. 52 mm Hg in db/db NS). TAC did not change LV end diastolic (ED) and end systolic (ES) diameter (D) in WT (2.80 mm vs. 2.87 mm and 1.17 mm vs. 1.21 mm after TAC) whereas db/db showed a significant increase (2.9 mm vs. 3.7 mm p<0.05 and 1.39 vs. 1.82 mm p<0.05). Beta adrenergic receptor (βAR) kinase 1 expression was significantly augmented in WT after TAC, but not in db/db, suggesting that other mechanisms rather than βAR dysfunction are responsible for the early LV dilatation. It is known that in WT CD8+ T cells contribute to collateral development after hind limb ischemia recruiting CD4+ T cells through IL-16 production. Moreover, disruption of coordinated tissue growth and angiogenesis in the heart contribute to the progression from adaptive cardiac hypertrophy to heart failure. In the present study we found a marked increase in CD4+, CD8+ T cells and interleukin-16 (IL-16) in WT hearts. CD4+CD8+ T cells recruitment and IL-16 production were significantly blunted in db/db suggesting that the consequent impaired angiogenic response after TAC could be responsible for the early LV dilatation.