Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats

Abstract

Although there is a correlation between hypertension and levels of interleukin (IL) 6, the exact role this cytokine plays in myocardial remodeling is unknown. This is complicated by the variable tissue and circulating levels of IL-6 reported in numerous experimental models of hypertension. Accordingly, we explored the hypothesis that elevated levels of IL-6 mediate adverse myocardial remodeling. To this end, adult male Sprague-Dawley rats were infused with IL-6 (2.5 microg . kg(-1) . h(-1), IP) for 7 days via osmotic minipump and compared with vehicle-infused, aged-matched controls. Left ventricular function was evaluated using a blood-perfused isolated heart preparation. Myocardial interstitial collagen volume fraction and isolated cardiomyocyte size were also assessed. Isolated adult cardiac fibroblast experiments were performed to determine the importance of the soluble IL-6 receptor in mediating cardiac fibrosis. IL-6 infusions in vivo resulted in concentric left ventricular hypertrophy, increased ventricular stiffness, a marked increase in collagen volume fraction (6.2% versus 1.7%; P<0.001), and proportional increases in cardiomyocyte width and length, all independent of blood pressure. The soluble IL-6 receptor in combination with IL-6 was found to be essential to producing increased collagen concentration by isolated cardiac fibroblasts and also played a role in mediating a phenotypic conversion to myofibroblasts. These novel observations demonstrate that IL-6 induces a myocardial phenotype almost identical to that of the hypertensive heart, identifying IL-6 as potentially important in this remodeling process.

Figure 1

(A) Representative photomicrographs of picrosirus red stained myocardium depicting the marked induction of interstitial collagen in hearts infused with IL-6 (right) relative to that in hearts infused with vehicle (left). (B) Graphic representation of left ventricular collagen volume fraction from vehicle and IL-6 infused groups. All values are mean ± SEM. * p < 0.001 vs. vehicle infused group.

Figure 2

Left ventricular end-diastolic pressure-volume (P-V) relationships for IL-6 and vehicle infused groups. *p<0.001 vs vehicle infused group at the corresponding pressure.

Figure 3

Myocardial levels of IL-6 (A) and TNF-α (B) following vehicle and IL-6 infusions. All values are mean ± SEM. * p < 0.001 vs. vehicle infused group.

Figure 4

Hydroxyproline synthesis by isolated adult cardiac fibroblasts following treatment with IL-6 (10 ng/mL, A; 50 ng/mL, B) in the presence of increasing concentrations of the sIL-6R. (C) Representative Western blot analysis and quantification (D) of α-SMA levels in isolated adult cardiac fibroblasts following treatment with IL-6 and sIL-6R. All values are mean ± SEM. *= p < 0.05 vs control; †=p < 0.05 vs IL-6.