CD40‐CD40 ligand (CD40L) signaling modulates cardiac hypertrophy in angiotensin‐II induced hypertensive heart disease

Abstract

The co‐stimulatory dyad CD40‐CD40L is involved in pro‐inflammatory activation of a wide range of immune and non‐immune cells. Here we investigated whether CD40‐CD40L interactions attenuate cardiac hypertrophy in hypertensive heart disease. Therefore CD40 knockout and wild type C57Bl6‐J mice were treated with angiotensin II (AngII) (2.5 mg/kg/day) for 4 weeks. AngII‐induced hypertension led to a significant increase in cardiac mass in Wt mice (+31%, P<0.01), but not in CD40 knockout mice (+10%, N.S.). Comparable changes were observed in diastolic wall thickness (echocardiography) and cardiomyocyte cross sectional area. To determine which CD40‐TRAF interactions were involved, the effect of mutations in the intracellular TRAF binding domains of CD40 was investigated. Relative to mice with intact downstream CD40 signaling, disruption of TRAF2/3/5, TRAF6 or both binding sites was associated with reduced hypertrophy (cardiac mass −24% for CD40‐TΔ2, −28% for CD40‐ TΔ6 and −26% in CD40‐TΔ2/6; p<0.05). Reduced hypertrophy was not associated with a decline in immune cell infiltration (CD45+ cells) or collagen content. Although the exact mechanism remains to be elucidated the present findings indicate that CD40‐ CD40L interactions are involved in the development of cardiac hypertrophy.