Phone: (914) 594-4153/3116
Department of Pharmacology
Basic Science Building, Rm. 514
15 Dana Road
Valhalla, NY 10595
Our research aimed at identifying the role of lipid autacoids, more specifically cytochrome P450 (CYP)-derived eicosanoids, in the regulation of inflammation and vascular function, and on determining their contribution to the pathogenesis of hypertension and cardiovascular, renal and metabolic diseases. Our laboratory was the first to characterize the CYP-derived 20-hydroxyeicosatetraenoic acid (20-HETE) as a potent vasoactive and inflammatory autacoid whose circulating levels are greatly elevated in hypertensive and obese (BMI>35) subjects and in animal models of hypertension and obesity. We have shown a direct relationship between the production of 20-HETE and blood pressure in animal models of hypertension. We also showed association between urinary 20-HETE excretion and salt-sensitive hypertension in humans.
We have identified 20-HETE as the mediator of androgen-dependent hypertension and a potent endogenous regulator of the angiotensin-converting enzyme (ACE) as well as a key determinant of microvascular dysfunction and remodeling in hypertension. The cellular mechanism underlying the androgen-induced increase in blood pressure and susceptibility to cardiovascular morbidity is not completely known. Studies are aimed at understanding 20-HETE cellular and molecular mechanisms of action with the goal of uncovering novel therapeutic targets (e.g., 20-HETE receptor) for the treatment of cardiovascular complications in hypertension, especially hypertension driven by increased androgen levels that not only occur in men but is also believed to underlie the increased susceptibility to hypertension in menopausal women and in conditions such as the polycystic ovary syndrome. The experimental approach is multi-faceted and includes the use of transgenic mice and genetically modified rats as well as molecular and pharmacological probes together with cell culture models.
Garcia V, Gilani A, Shkolnik B, Pandey V, Zhang FF, Dakarapu R, Gandham SK, Reddy NR, Graves JP, Gruzdev A, Zeldin DC, Capdevila JH, Falck JR and Schwartzman ML. 20-HETE Signals Through G Protein-Coupled Receptor GPR75 (Gq) to Affect Vascular Function and Trigger Hypertension. Circ Res. 2017.
Garcia V, Joseph G, Shkolnik B, Ding Y, Zhang FF, Gotlinger K, Falck JR, Dakarapu R, Capdevila JH, Bernstein KE and Schwartzman ML. Angiotensin II receptor blockade or deletion of vascular endothelial ACE does not prevent vascular dysfunction and remodeling in 20-HETE-dependent hypertension. Am J Physiol Regul Integr Comp Physiol. 2015;309:R71-8.
Wu CC, Gupta T, Garcia V, Ding Y, Schwartzman ML. 20-HETE and blood pressure regulation: Clinical implications. Cardiol Rev. 2014;22:1-12
Wu CC, Mei S, Cheng J, Ding Y, Weidenhammer A, Garcia V, Zhang F, Gotlinger K, Manthati VL, Falck JR, Capdevila JH, Schwartzman ML. Androgen-sensitive hypertension associates with upregulated vascular cyp4a12-20-hete synthase. J Am Soc Nephrol. 2013
Cheng J, Garcia V, Ding Y, Wu CC, Thakar K, Falck JR, Ramu E, Schwartzman ML. Induction of angiotensin-converting enzyme and activation of the renin-angiotensin system contribute to 20-hydroxyeicosatetraenoic acid-mediated endothelial dysfunction. Arterioscler Thromb Vasc Biol. 2012;32:1917-1924
Schwartzman ML, Iserovich P, Gotlinger K, Bellner L, Dunn MW, Sartore M, Grazia Pertile M, Leonardi A, Sathe S, Beaton A, Trieu L, Sack R. Profile of lipid and protein autacoids in diabetic vitreous correlates with the progression of diabetic retinopathy. Diabetes. 2010;59:1780-1788
Laffer CL, Gainer JV, Waterman MR, Capdevila JH, Laniado-Schwartzman M, Nasjletti A, Brown NJ, Elijovich F. The t8590c polymorphism of cyp4a11 and 20-hydroxyeicosatetraenoic acid in essential hypertension. Hypertension. 2008;51:767-772