Small molecule-mediated inhibition of CD40-TRAF6 reduces adverse cardiac remodelling in pressure overload induced heart failure. (15th March 2019)

• Record Type: Journal Article
• Authors: Bosch, Lena; de Haan, Judith; Seijkens, Tom; van Tiel, Claudia; Brans, Maike; Pasterkamp, Gerard; Lutgens, Esther; de Jager, Saskia
• Is Part Of: International journal of cardiology. Volume 279(2019)
• Page Start: 141
• Page End: 144
• Publication Date: 2019-03-15
• Subjects: Inflammation -- Heart failure -- Basic science research -- Animal models cardiovascular disease; Cardiology -- Periodicals; Electronic journals; 616.12
• DOI: 10.1016/j.ijcard.2018.12.076
• Languages: English
• ISSNs: 0167-5273

Abstract

Abstract: Background: CD40 signalling is involved in chronic inflammation, a condition that plays an important role in non-ischemic heart failure (HF). Small molecule inhibitors of CD40-TRAF6 have shown to be effective in multiple animal-models of chronic inflammatory disease, such as obesity and atherosclerosis. Methods & results: Mice were subjected to transverse aortic constriction (TAC) and randomized to small molecule inhibition of CD40-TRAF6 or placebo. CD40-TRAF6 inhibition resulted in less cardiac remodelling 10 weeks after TAC with a reduced end systolic volume (TAC-placebo group: 71.9 ± 8.8 vs TAC-CD40-TRAF6 inhibitor: 53.7 ± 6.1 μl, p = 0.03) and improved ejection fraction (EF) compared to placebo (TAC-placebo group: 25.6 ± 2.8 vs TAC-CD40-TRAF6 inhibitor: 35.5 ± 3.3%, p = 0.02). Within the myocardium, CD40-TRAF6 inhibition resulted in decreased macrophage and T-cell infiltration 10 weeks after TAC compared to placebo. In addition, a decrease in fibrosis and cardiomyocyte hypertrophy was observed in the CD40-TRAF6 inhibitor group compared to placebo. Conclusion: CD40-TRAF6 inhibition improves cardiac function in non-ischemic HF in mice. This effect is mediated by a reduction in macrophage and T-cell influx in the myocardium, accompanied by a reduction in cardiac fibrosis and hypertrophy. Highlights: CD40-TRAF6 signalling is involved in adverse cardiac remodelling CD40-TRAF6 inhibition improves cardiac function in non-ischemic heart failure in mice CD40-TRAF6 inhibition after TAC leads to a reduction in macrophage and T-cell influx in the myocardium Co-stimulatory molecules are possible therapeutic targets for non-ischemic heart failure