Circadian clock in angiotensin II induced hypertension

Hypertension is a major risk factor for cardiovascular disease, end-organ damage, and death. Despite the numerous treatment paradigms targeting the control mechanisms in blood pressure (cardiac function, vascular tone, water balance and autonomic outflow, ) management of blood pressure remains a major challenge. The circadian clock has emerged as an important mechanism that also controls blood pressure. The circadian clock, the molecular basis of 24-hour timing, consists of a transcriptional, translational, and post-translational feedback loop generated by a unique set of genes and proteins. We have found that isolated blood vessels exhibit rhythms in these genes and that dysfunction in the circadian clock can lead to dysfunction in the vasculature. Recent data has demonstrated the importance of the genetic components of the circadian clock in blood pressure control and rhythm. However, it remains unclear how and if the circadian clock conditions the response to experimental hypertension. In preliminary data, I have discovered that Angiotensin II induces non-dipping hypertension in circadian clock knockout mice. Thus, I hypothesize that AngII dependent hypertension is exacerbated by circadian clock dysfunction. Moreover, I have found that two key targets that mediate Ang II-induced hypertension are impaired in circadian clock mutant mice: superoxide production and salt balance. Thus, I will determine the contribution of superoxide and salt balance on the hypertensive phenotype in Per-knockout mice. Finally, I propose to test if a novel agent that stimulates the circadian clock (Rev-erb a agonist) lowers blood pressure and restores rhythmic blood pressure in WT and circadian clock mutant mice. (AHA Program: Predoctoral Fellowship)