El-Shewy Pilot Project El-Shewy Pilot Project

Pilot Project Awarded 2013

Hesham M. El-Shewy, Ph.D.
Research Assistant
Professor College of Medicine

Project Summary:
Hypertension is a chronic condition associated with increased risk of mortality and morbidity from stroke, coronary heart disease, congestive heart failure, and chronic renal disease. Difficulty in controlling hypertension is due, in part, to the complexity of the pathophysiology of hypertension. In addition to the involvement of multiple pathways and feedback mechanisms, hypertension is often associated with other pathological conditions such as renal dysfunction, which is tightly linked to the renin-angiotensin system (RAS). Angiotensin (AngII), an important regulator of RAS, plays a critical role in regulation of blood pressure and volume homeostasis. These effects are mediated mainly via Ca2+ mobilization. Investigators reported the involvement of sphingosine kinase 1 (SK1) and its bioactive sphingolipid, sphingosine 1-phosphate (S1P) in the mobilization of intracellular Ca2+ and regulation of vascular tone. However, the exact mechanism is poorly understood. Here, we tested the role of SK1in AngII-stimulated Ca2+ release and vascular tone. Our early observation using different cell lines indicated a characteristic pattern of AngII induced increase in intracellular Ca2+ level, an immediate peak followed by a sustained Ca2+ influx via store-operated Ca2+ channel (SOC). Inhibition or genetic deletion of SK1 abolished the transmembrane Ca2+ influx phase suggesting a role of SK1 in AngII-dependent SOC activation. In vivo experiments revealed that deletion of SK1 significantly reduced rise of blood pressure by acute as well as chronic infused AngII in mice. The central hypothesis of this proposal is that SK1 activation plays a key role in the AngII induced intracellular Ca2+ mobilization and thereby regulates vascular tone and renal microvascular hemodynamic and blood pressure. The proposal is organized into two Specific Aims. Aim one is to elucidate the molecular mechanism underlying SK1-mediated regulation of intracellular Ca2+ mobilization. Aim 2: To test whether genetic deletion of SK1 will affect the AngII response on blood pressure. Using these physiologically relevant models, these studies will enable us to gain important insights into the role of SK1 pathway in regulation of vascular tone that may lead to novel therapeutic targets for treatment of cardiovascular diseases related to defective vascular tone such as hypertension.