Abstract

The expression of Calcium/calmodulin-dependent kinase IV (CaMKIV) was so far thought to be confined to the nervous system. Recent studies have indicated its presence in the endothelium, suggesting a role for this kinase in the regulation of vascular tone. Moreover, genome-wide analysis has shown an association between elevated blood pressure (BP) and the rs10491334 single nucleotide polymorphism of human CaMKIV gene (CaMK4). To directly assess the role of CaMKIV in hypertension, we characterized the cardiovascular phenotype of CaMK4-/- mice. They presented higher BP levels compared with CaMK4+/+ littermates, showing also a typical hypertensive phenotype, including endothelial dysfunction, cardiac hypertrophy, vascular and kydney damage and impaired angiogenesis. In cultured endothelial cells isolated from the aorta of CaMK4+/+ mice, CaMK4 co-immunoprecipitates with eNOS and phosphorylates it in Ser1177. These responses are lost in CaMK4-/- endothelial cells, in which, interestingly, eNOS activity was reduced. Furthermore, we found that the rs10491334 variant causes a reduction in the expression levels of CaMKIV in lymphocytes from hypertensive patients. Taken together, our results provide evidence that CaMKIV plays a pivotal role in BP regulation through the control of eNOS activity.