The long-term research goal of my laboratory is the elucidation of mechanisms by which eicosanoid metabolites influence cardiovascular function. Over the past decade considerable interest has focused on the eicosanoid pathway. Substantial evidence has accumulated demonstrating that eicosanoid metabolites are involved in the regulation of vascular function and contribute to the integration of cardiovascular function. Altered production of eicosanoid metabolites contributes to the pathology associated with many diseases including hypertension, diabetes, cardiometabolic syndrome and stroke. Although the importance of the eicosanoid pathway is now well recognized, many aspects concerning cell-signaling and pathophysiological role of eicosanoid metabolites remain unresolved. Ongoing investigations of eicosanoid metabolites in the laboratory have led to the discovery of novel therapeutic targets for cardiovascular diseases.
1. EETs and Epoxide Hydrolase as a Therapeutic Target for Cardiovascular Diseases
One out of every four adults in the United States has hypertension and is at increased risk for the development of coronary artery disease, stroke, congestive heart failure, and end stage renal disease (ESRD). Although great strides have been made in providing more effective treatments of hypertension, kidney damage still progresses during high blood pressure and the incidence of ESRD associated with hypertension is escalating. Another disease that is influenced by hypertension is stroke and this acute ischemic stroke is the third leading cause of death in the United States. The long-term objective of this project is the elucidation of mechanisms by which epoxyeicosatrienoic acids (EETs) and the epoxide hydrolase enzyme influence renal and cerebral vascular function in hypertension. The proposed studies are employing newly developed and innovative pharmacological compounds that target epoxyeicosanoids to determine their ability to lower arterial blood pressure and improve renal vascular function and decrease stroke induced brain damage in hypertension.
2. Eicosanoid Metabolites and End Organ Damage in Obesity & Diabetes
Obesity contributes significantly to the development of certain diseases like diabetes and hypertension. Obesity is the central phenotype in cardiometabolic syndrome that clusters with other cardiovascular risk factors. These other risk factors include hypertension, type 2 diabetes, insulin resistance, low HDL cholesterol, elevated triglycerides, microalbuminuria, and atherosclerosis. A major cause of morbidity and mortality is the progression of end organ damage in obesity, diabetes and hypertension. Hypertension and obesity are both associated with a complex systemic inflammatory state that has been implicated in common medically important complications including endothelial dysfunction and insulin resistance. Altered epoxide metabolite production could be a major contributing factor to the endothelial dysfunction and inflammation associated with hypertension and obesity. This project utilizes unique animal models of disease and genetically modified animals to focus on the contribution of epoxide metabolites to vascular damage in cardiometabolic syndrome.
3. Vascular Cellular Signaling Mechanisms Utilized by Eicosanoid Metabolites
The long-term objective of this research project is to test the general hypothesis that controlled generation of specific eicosanoid metabolites provides important mediators of vascular function. We have established that EETs produced by the endothelium have anti-hypertensive properties and that the epoxides 11,12-EET and 14,15-EET are endothelium-derived hyperpolarizing factors (EDHFs). On the other hand, the hydroxylase metabolite, 20-HETE, is produced by vascular smooth muscle cells, causes vasoconstriction and has been implicated as a pro-hypertensive factor. Identification of the cell signaling pathways involved in the response to eicosanoid metabolites and their role in hormonal and paracrine regulation of the vasculature remains unresolved. This project integrates current knowledge of the functional significance of the vascular eicosanoid pathway with advances in genetic and biomolecular approaches to describe the mechanism of action of 11,12-EET and 14,15-EET and 20-HETE and the determine importance of this pathway.
4. Endothelial Dysfunction in Salt-Sensitive Hypertension
A contributing factor to hypertension and the resulting end organ damage is an impaired endothelium. There is convincing evidence that endothelial dysfunction is linked to end organ damage in human essential and salt-sensitive hypertension. Vascular EET production increases in response to high dietary salt and is inappropriately low during the development of salt-sensitive hypertension. EETs are EDHFs and epoxides have anti-hypertensive and anti-inflammatory properties that could protect the vasculature during cardiovascular disease states. Cytokine suppression of epoxygenase enzymes is a mechanism that could account for decreased EET production and organ damage associated with salt-sensitive hypertension. These studies suggest that pharmacological or genetic manipulation of these pathways could be potential therapies in human hypertension. We are utilizing novel pharmacological approaches and organ and cell specific genetically modified animals. This project focuses on the specific contribution of inappropriate epoxide regulation to endothelial dysfunction and end organ damage in salt-sensitive hypertension and is providing novel information on the interaction between cytokines and epoxide levels in salt-sensitive hypertension.
Olearczyk JJ, Quigley JE, Mitchell B, Yamamoto T, Kim IH, Newman JW, Laurie A, Hammock BD, Imig JD. Inhibition of the soluble epoxide hydrolase protects the kidney from damage in hypertensive Goto-Kakizaki rats. Clinical Science 116:61-70, 2009. PMID: 18459944
Simpkins AN, Rudic RD, Schreihofer DA, Roy S, Manhiani M, Tsai HJ, Hammock BD, Imig JD. Soluble epoxide hydrolase inhibition is protective against cerebral ischemia via vascular and neural protection. American Journal of Pathology 174:2086-2095, 2009. PMID: 19435785
Manhiani MM, Quigley JE, Knight SF, Tasoobshirazi S, Moore T, Brands MW, Hammock BD, Imig JD. Soluble epoxide hydrolase gene deletion attenuates renal injury and inflammation in DOCA-salt hypertension. Am J Physiol Renal Physiol 297:F740-F748, 2009. PMID: 19553349
Imig JD, Hammock BD. Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nat Rev Drug Discov 8:794-805, 2009. PMID: 19794443
Elmarakby A, Imig JD. Obesity is the major contributor to vascular dysfunction and inflammation in high fat diet hypertensive rats. Clinical Science 118:291-301, 2010. PMID: 19728860
Knight SF, Yuan J, Roy S, Imig JD. Simvastatin and tempol protect against endothelial dysfunction and renal injury in a rat model of obesity and hypertension. Am J Physiol Renal Physiol 298:F86-F94, 2010. PMID: 19906952
Simpkins AN, Rudic RD, Roy S, Tsai HJ, Hammock BD, Imig JD. Soluble epoxide hydrolase inhibition attenuates vascular remodeling. Am J Physiol Heart Circ Physiol 298:H795-H806, 2010. PMID: 20035028
Sudhahar V, Shaw S, Imig JD. Epoxyeicosatrienoic acid analogs and vascular function. Curr Med Chem 17:1181-1190, 2010. PMID: 20158473
Lee CR, Imig JD, Edin ML, Foley J, DeGraff LM, Bradbury JA, Graves JP, Lih FB, Clark J, Myers P. Perrow L, Lepp AN, Kannon A, Ronnekleiv OK, Alkayed NJ, Falck JR, Tomer KB, Zeldin DC. Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice. FASEB J May 21, 2010. [Epub ahead of print] PMID: 20495177