Zipper‐interacting protein kinase is a key regulator of vascular smooth muscle tone with implications in development of hypertension (676.18)

Abstract

Essential hypertension is linked to increased contractile tone in the resistance vasculature and affects ~25% of adults, increasing their risk for more severe cardiovascular disease. Recently, zipper‐interacting kinase (ZIPK) was linked to essential hypertension in animal models of the disease. We possess a novel inhibitor of ZIPK that lacks off‐target effects against other contractile kinases and is uniquely situated to investigate the role of ZIPK in normal and pathological vascular smooth muscle function. Hypothesis: ZIPK contributes to the Ca2+ sensitization of vascular smooth muscle, which is in turn accentuated in hypertensive disease states. We used isolated ex vivo vessels with pressure myography, along with the ZIPK inhibitor HS38, to investigate cerebral vessels isolated from human biopsies and spontaneously hypertensive rats (SHR). ZIPK was expressed in human cerebral vessels and contributes to the myogenic response to pressure. Treatment with HS38 resulted in a ~60% reduction in the magnitude of myogenic contractions over the 60‐120mmHg pressure range. Moreover, when early‐stage SHR were compared, we found the myogenic response was enhanced with an increase in the contribution of ZIPK. Based on these findings, we conclude that ZIPK is a critical factor in the development of essential hypertension, and represents a unique and viable, therapeutic target in humans.