CCL17 acts as a novel therapeutic target in pathological cardiac hypertrophy and heart failure

Abstract

Circulating proteomic signatures of age are closely associated with aging and age-related diseases; however, the utility of changes in secreted proteins in identifying therapeutic targets for diseases remains unclear. Serum proteomic profiling of an age-stratified healthy population and further community-based cohort together with heart failure patients study demonstrated that circulating C-C motif chemokine ligand 17 (CCL17) level increased with age and correlated with cardiac dysfunction. Subsequent animal experiments further revealed that Ccll7-KO significantly repressed aging and angiotensin II (Ang II)–induced cardiac hypertrophy and fibrosis, accompanied by the plasticity and differentiation of T cell subsets. Furthermore, the therapeutic administration of an anti-CCL17 neutralizing antibody inhibited Ang II–induced pathological cardiac remodeling. Our findings reveal that chemokine CCL17 is identifiable as a novel therapeutic target in age-related and Ang II–induced pathological cardiac hypertrophy and heart failure.

The chemokine CCL17 is a novel therapeutic target for cardiovascular aging

“… 3 Here we demonstrated that CCL17 is a key regulator of vascular aging and CCL17 could serve as a therapeutic target. Previous works from our laboratory and other scientists have demonstrated that CCL17 regulated T cells to promote cardiac aging, 6 , 9 which may be also the potential mechanism underlying vascular aging because we observed such reprogramming of the immune microenvironment (T cells balance) in vascular aging. Further in-depth analysis is still needed to explore CCL17 in reprogramming the immune microenvironment during cardiovascular aging.…”

“…The serum CCL17 level was increased by Ang II infusion but diminished by CCL17-neutralizing antibodies without any effects on blood pressure or heart rate (Supplementary Tables 2 and 3 ). 6 CCL17 antibody repressed Ang II-induced vascular arterial stiffness and constriction-relaxation dysfunction (Fig. 1h, i ), and reduced aortic remodeling, fibrosis, cell senescence, and senescence-associated secretory phenotype, elastin fiber breakage, coupled with reprogrammed immune microenvironment (Fig.…”

“…Our previous study demonstrated the involvement of helper T (Th) cells in CCL17 function during cardiac aging. 6 Indeed, Ccl17 knockout reduced aging-induced infiltration of total immune cells and CD4 + T cells in aged aortas. Notably, aging-induced expression of Th1 markers (T-bet, IL-2) as well as Th2 markers (IL-4, IL-13) in aortas, while Ccl17 knockout increased the overexpression of Th1 markers but reduced Th2 markers in aged aortas (Fig.…”

“…We previously demonstrated the involvement of the dendritic cell chemokine CCL17 in coronary artery diseases and cardiac aging. 6 , 7 But the pathological functions of CCL17 in vascular aging remain unknown. To investigate the potential pathological roles of CCL17 in vascular biology and diseases, we used a community cohort in the Shunyi district (Beijing, China) enrolling over 1000 participants.…”

“…8e ), which was consistent with our findings in aged hearts. 6 Thus, CCL17 may regulate Th cells to reprogram the immune microenvironment and act as the orchestrator of vascular aging.…”