Myeloid MyD88 Mediates Macrophage Infiltration and Activation in Ang II-Induced Cardiac Hypertrophy

Hypertension is the leading cause of cardiac remodelling and heart failure. Recent evidence has highlighted the role of the non-hemodynamic function of angiotensin II in hypertension. MyD88 is the canonical adaptor of TLRs and IL-1Rs, which serves as the central node in regulating inflammatory responses. Previous studies reported the opposite roles of MyD88 in hypertension. In this study, we aimed to determine the role of MyD88 and the underlying mechanisms in hypertension. Cardiomyocyte-specific MyD88 knockout mice, macrophage-specific MyD88 knockout mice, and MyD88 inhibitor-treated mice were challenged with Ang II infusion to establish a cardiac remodelling model. An inflammatory cytokine array was used to determine the internal mediators. Our results showed that cardiomyocyte MyD88 deficiency showed little protection, whereas macrophage MyD88 deficiency and pharmacological MyD88 inhibition using LM8 significantly ameliorated Ang II-induced cardiac inflammation, fibrosis, and dysfunction. The cytokine and chemokine array demonstrated that CXCL1 and CCL2 were differentially expressed between cardiomyocyte-specific MyD88 knockout and macrophage-specific MyD88 knockout mice. Deletion of MyD88 in macrophages significantly decreased macrophage infiltration and suppressed the activation of macrophages, which then reduced the conditioned medium-induced cardiomyocyte hypertrophy. Our study demonstrated that targeting myeloid MyD88 could be a potential strategy in treating hypertensive cardiac remodelling.

MyD88; angiotensin II; hypertrophy; inflammation; macrophages.