MyD88 in myeloid cells drives angiotensin II-induced vascular inflammation, is associated with prevalent heart failure and predicts all-cause mortality in arterial hypertension

Abstract Background Angiotensin II (AngII) causes hypertension and vascular inflammation cells and is essential in neurohumoral activation promoting the development of heart failure. The role of the adaptor protein myeloid factor of differentiation 88 (MyD88) driving this pathology remains incompletely understood. Methods Male C57BL/6JMyD88-/-, LysMCre/wtMyD88LSL/LSL, LysMCre/wt, TLR2-/-, TLR4-/-, TLR7-/- and TLR9-/- mice were investigated (1mg/AngIIkg/d for 7 days). Additionally, we performed biodata analyses from a population-based cohort study and human protein network interactome analyses to understand the role of MyD88 in hypertension. Results MyD88 deficiency attenuated AngII-induced hypertension and endothelial dysfunction in conductance and resistance vessels, surpassing the effect of single TLR-deficiencies. Vascular mRNA expression levels of vcam-1, nos2, nox2, cd62L, cd68, ccl2, il12 and il1b, and accumulation of CD11b+Ly6Chi inflammatory monocytes and interferon-g+ NKcells were significantly dampened in MyD88-/-. Vascular protection was conferred by MyD88 deficiency in bone marrow derived cells. Re-expression of MyD88 in LysMCre/wtMyD88LSL/LSL mice restored AngII-induced pathology, revealing that myeloid cells drive vascular dysfunction in a MyD88-dependent manner. Computational analyses of the human protein interactome demonstrated that MyD88 expression significantly associates with proteins encoded by genetic loci associated with blood pressure traits in multiple GWAS. In hypertensive individuals of the Gutenberg-Health Study, monocytic MyD88 mRNA expression was associated with prevalent heart failure and all-cause mortality after a median follow-up of 16.5 years. Conclusion MyD88 promotes AngII-induced vascular dysfunction and arterial hypertension and might serve as both an inflammatory diagnostic marker and a drug target to tackle the risk of death and incident heart failure in hypertensive patients.