Molecular Interactions Between Angiotensin II and Endocannabinoid Receptors

Grant Winners

Deans

Abstract

Hypertension is the single most decisive risk factor for cardiovascular disease. Termed the silent killer, hypertension has a telling impact on global survival rates. Therefore, discovering unique therapeutic targets is important as it lays the groundwork for improving antihypertensive drug therapy. In order to achieve this, understanding the molecular mechanisms involved in the dysregulation of blood pressure regulatory components, is critical. Hence, we propose to study certain key components, not as distinct, but as coordinated and interlinked systems. The systems under investigation are the Renin Angiotensin system (RAS) and the Endocannabinoid system (eCS). Angiotensin (Ang) II,an active peptide of the RAS, plays an important role in mediating the deleterious effects of hypertension, primarily through actions at the AT1 receptor (AT1R). New evidence has surfaced that establishes a link between Ang II and the Cannabinoid Type 1 Receptor (CB1R) of the eCS, a receptor that is highly expressed in the brain. In fact, this receptor has been demonstrated to be up-regulated in hypertensive rat models. We hypothesize that there is an interaction between the AT1R and the CB1R in the brain, and this is dysregulated in hypertensive conditions. Primary astrocytecultures isolated from hypertensive and normotensive rats will be our model system. The objectives of this project are to determine the expression levels of the CB1R and the AT1R in the presence of Ang II and the CB1R agonist, respectively. Along with the molecular mechanisms governing the two receptor interactions (transactivation), the functional significance of the interaction will also be investigated. These studies will not only establish whether the two systems interact in a synergistic or an antagonistic manner, but also whether this interaction is different in the hypertensive state. These studies will provide a better understanding of the role of the brain as a key blood pressure regulatory organ.