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Principal Investigator: Kim Tran
Organization: DES MOINES UNIV OSTEOPATHIC MEDICAL CTR
Fiscal Year: 2024
Award: $453,404
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Reduced nitric oxide (NO) availability is a common pathophysiological feature of many cardiovascular
diseases. While NO donors are used, significant issues limit their utility, including the development of nitrate
tolerance and endothelial dysfunction. Although intermittent nitrate therapy is common practice, this strategy has
limitations and is not considered a solution to nitrate tolerance issues. Extensive intravenous use of sodium
nitroprusside is associated with a risk for cyanide poisoning. There is thus a strong need to identify new
approaches to promote endogenous NO production. The stromal interaction molecule 1 (STIM1), a Ca2+-sensing
protein in the endoplasmic reticulum (ER), is a critical determinant of store-operated Ca2+ entry, which in
endothelial cells (ECs) is required for sustained endogenous NO production. Vascular smooth muscle-specific
STIM1 deletion blunted hypertension and cardiac hypertrophy caused by angiotensin II. In contrast, endothelial
STIM1 is predictably important for vasorelaxation, such that EC-specific STIM1 deletion attenuates endothelium-
dependent vasodilation and increases blood pressure. However, no strategy currently exists to directly target
endothelial STIM1 for clinical benefit.
In this application, we propose to develop a novel vasorelaxing peptide (EFG2) that acts by promoting
endogenous NO production and has several unique properties that are of potential clinical benefit. Our peptide
is derived from the G protein-coupled estrogen receptor, is designed to be specific for the endothelium, and
directly targets STIM1 to trigger endothelial Ca2+ entry without depleting ER Ca2+ store, thereby stimulating
endogenous NO production while protecting ER function. Our objectives in this proposal are to delineate the
mechanisms of action of EFG2 in endothelial cells, assess its effects on several aspects of EC function, begin
testing its potential as a vasorelaxing agent using a model of hypertension, and through these studies, provide
training for students in the graduate and medical programs at DMU. Three specific aims are proposed. AIM 1
will delineate the mechanisms of action of EFG2 in endothelial cells, by testing its ability to activate the
prototypical ICRAC current and document its target domains on STIM1 that are responsible for its effect to trigger
endothelial Ca2+ entry. AIM 2 will assess the effects of EFG2 on several aspects of EC function, by testing the
hypotheses that EFG2 promotes eNOS activity, reduces inflammation-induced expression of vascular adhesion
molecules and smooth muscle proliferation, but does not cause ER stress. AIM 3 will test the hypothesis that
EFG2 reduces blood pressure in hypertensive rats in a NO-dependent fashion.
Completion of the studies will introduce a mechanistically novel vasorelaxing peptide with several unique
features that are of potential clinical benefit, provide quality student training, and enhance overall research
outcomes of Des Moines University.
Terms: <Adhesion Molecule><Affect><Affinity><Agonist><Anesthesia><Anesthesia procedures><AngII><Angiotensin II><Antigenic Determinants><Antiinflammatory Effect><Aorta><Apoplexy><Attenuated><BP reduction><Binding><Binding Determinants><Blood Vessels><Brain Vascular Accident><CMKRL2><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chemokine Receptor-Like 2><Clinical><Common Rat Strains><Cyanides><Cytoplasm><Data><Data Analyses><Data Analysis><Development><Disodium Salt Nitroprusside><Dysfunction><ER stress><ERalpha><ERα><ESR1><ESR1 gene><Endogenous Nitrate Vasodilator><Endoplasmic Reticulum><Endothelial Cells><Endothelium><Endothelium-Derived Nitric Oxide><Epitopes><Ergastoplasm><Estradiol Receptor alpha><Estradiol Receptor α><Estrogen Receptor 1><Estrogen Receptor alpha><Estrogen Receptor α><Estrogens><Event><Functional disorder><G Protein-Coupled Estrogen Receptor><G Protein-Coupled Receptor 30><GPER><GPER gene><GPR30><Goals><Heart Hypertrophy><Heart Vascular><Heart failure><Hypertension><Inbred SHR Rats><Inflammation><Intracellular Communication and Signaling><Intravenous><Investigators><Involuntary Muscle><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Leiomyocyte><MD students><Mediating><Medical><Medical Students><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Modeling><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mononitrogen Monoxide><Myocardial Ischemia><NO3-><NR3A1><Nitrates><Nitric Oxide><Nitric Oxide Donors><Nitrogen Monoxide><Nitrogen Protoxide><Outcomes Research><Penetration><Peptides><Physiopathology><Poisoning><Process><Production><Proliferating><Property><Proteins><Publications><Rat><Rats Mammals><Rattus><Receptor Protein><Research Personnel><Researchers><Risk><SHR Rats><STIM1><STIM1 gene><Scientific Publication><Signal Transduction><Signal Transduction Systems><Signaling><Smooth Muscle><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Sodium Nitroprusside><Spontaneously Hypertensive Rats><Stroke><Stromal Change><Stromal Interaction Molecule 1><Subcellular Process><Surface Proteins><Testing><Therapeutic><Therapeutic Estrogen><Universities><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascular Smooth Muscle><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasodilatation><Vasodilation><Vasopressor Agents><Vasorelaxation><Work><anti-inflammatory effect><attenuate><attenuates><biological signal transduction><blood pressure elevation><blood pressure reduction><brain attack><cardiac failure><cardiac hypertrophy><cardiac ischemia><cardiovascular disorder><cell adhesion protein><cerebral vascular accident><cerebrovascular accident><circulatory system><clinical efficacy><conformation><conformational><conformational state><conformationally><conformations><coronary ischemia><cytokine><data interpretation><design><designing><developmental><dimer><elevated blood pressure><endoplasmic reticulum stress><endothelial cell derived relaxing factor><endothelial dysfunction><graduate student><heart ischemia><high blood pressure><hyperpiesia><hyperpiesis><hypertensive><hypertensive disease><hypertensive disorder><increase in blood pressure><increased blood pressure><intravenous injection><lower BP><lower blood pressure><lowers blood pressure><medical school students><myocardial ischemia/hypoxia><myocardium ischemia><neutralizing antibody><new approaches><nitrate><normotensive><novel><novel approaches><novel strategies><novel strategy><pathophysiology><poisoned><programs><receptor><reduce BP><reduce blood pressure><reduction in BP><reduction in blood pressure><response><spontaneous hypertensive rat><stroked><strokes><student training><success><vascular><vascular constriction><vasoconstriction><vasopressor><voltage>