This proposal seeks to test the hypothesis that the specific activation of the G-protein-coupled receptor GPR75 (Gq) in the endothelium and vascular smooth muscle is central to the mechanisms underlying 20-HETE- dependent vascular dysfunction and hypertension. The foundation for this hypothesis stems from studies implicating the cytochrome P450 (CYP) 4-derived 20-HETE in setting the level of systemic arterial blood pressure (BP), in human subjects and experimental animals, via actions on vascular and renal structures. We demonstrated that pharmacological and genetic interventions that increase synthesis of 20-HETE in rodents also cause elevation of BP. Conversely, the BP of hypertensive rodents, featuring increased 20-HETE synthesis, was diminished by pharmacological or genetic manipulations that interfere with the synthesis or the action of this eicosanoid, thus providing compelling evidence that 20-HETE contributes importantly to pro- hypertensive mechanisms. Previous and preliminary studies, have shown that conditional overexpression of Cyp4a12 (the murine 20-HETE synthase) selectively in endothelial cells (EC) or vascular smooth muscle cells (VSMC) prompts development of hypertension in mice, raising the intriguing possibility that the mechanism(s) underlying 20-HETE-induced hypertension vary with cell type targeted by this eicosanoid. It also raises the possibility of the presence of a common target/receptor that governs distinct cell-specific 20-HETE-triggered signaling pathways leading to complex functional outcomes, including endothelial dysfunction, ACE induction/RAS activation, inflammation, smooth muscle contraction and vascular remodeling; all of which contribute to BP regulation. In this regard, we have exciting preliminary data demonstrating the identification of a G-protein coupled receptor (GPCR), GPR75 (Gq), an orphan GPCR, as the putative 20-HETE receptor. We show that: 1) 20-HETE specifically binds to EC membranes and this binding is negated in GPR75-deficient membranes; 2) 20-HETE stimulates GPR75-G?q/11 dissociation in EC and VSMC and intracellular i[Ca2+] accumulation in EC; 3) GPR75 knockdown negates 20-HETE-stimulated EGFR phosphorylation, the initial signaling step of 20-HETE in EC; 4) GPR75 is expressed in tissues where 20-HETE exerts its actions (EC, VSMC, renal arteries and kidney); and 5) In vivo knockdown of GPR75 prevents DOX-induced 20-HETE-driven BP elevation, endothelial dysfunction, smooth muscle contractility and vascular remodeling in Cyp4a12tg mice. Accordingly, we postulate that 20-HETE binds to GPR75 and triggers cell-specific signal transduction pathways leading to endothelial dysfunction, ACE upregulation, smooth muscle contractility and vascular remodeling, all of which contribute to hypertension We propose four aims that systematically determine the proximal signaling of GPR75-20-HETE pairing in EC and VSMC and assess the importance of GPR75 activation to the hypertension driven by increased 20-HETE production.
Hypertension is the leading cause of stroke and cardiovascular diseases and the chief risk factor for global disease burden. With few exceptions, the molecular bases of the most common forms of human hypertension are yet to be defined and thus, the early diagnosis and clinical management remains challenging and mostly symptomatic, reflecting the complexity of a disease in which multiple environmental and genetic factors, as well as coexisting conditions contribute to a multifaceted etiology. Our preliminary findings are exciting and potentially of great significance as they bring a new player to the area of hypertension. Given the fact that 20- HETE exerts pronounced effects on the vasculature independent of the renin angiotensin system and blood pressure, pharmacological targeting of GPR75-20-HETE may serve as a valuable alternative or additive to current antihypertensive therapies, which fall short of treating the vascular complications associated with hypertension.
|Zhang, Xiaofan; El Demerdash, Nagat; Falck, John R et al. (2018) The contribution of TRPV1 channel to 20-HETE-Aggravated ischemic neuronal injury. Prostaglandins Other Lipid Mediat 137:63-68|
|Gilani, Ankit; Pandey, Varunkumar; Garcia, Victor et al. (2018) HIGH FAT DIET-INDUCED OBESITY AND INSULIN RESISTANCE IN CYP4A14-/- MICE IS MEDIATED BY 20-HETE. Am J Physiol Regul Integr Comp Physiol :|
|Rocic, Petra; Schwartzman, Michal Laniado (2018) 20-HETE in the regulation of vascular and cardiac function. Pharmacol Ther 192:74-87|
|Soler, Amanda; Hunter, Ian; Joseph, Gregory et al. (2018) Elevated 20-HETE in metabolic syndrome regulates arterial stiffness and systolic hypertension via MMP12 activation. J Mol Cell Cardiol 117:88-99|