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Stevan P. Tofovic, MD, PhD

Associate Professor
100 Technology Drive, Bridgeside Point Building I, Room 542
Bridgeside Point Building I, Room 542
Pittsburgh, PA 15219
tofovic@pitt.edu
Phone: 412-648-3363
Fax: 412-624-5070

Education

MD, University of Skopje School of Medicine, Yugoslavia, 1979
MS (Pharmacology), University of Skopje School of Medicine, Yugoslavia, 1984
PhD (Pharmacology), University of Skopje School of Medicine, Republic of Macedonia, 1992
Postdoctoral Fellowship (Clinical Pharmacology), Vanderbilt University School of Medicine, 1989

 
Headshot of Stevan P. Tofovic, MD, PhD
Dr. Tofovic has had a sustained interest in the development and characterization of complex animal models of cardiovascular and renal disease, with primary focus on pulmonary hypertension (PH), heart failure and diabetic nephropathy. Using these model systems, he studies the underlining pathophysiology of cardiovascular/renal diseases and evaluates new therapeutic modalities. His lab is one of the few laboratories in the country that are studying the effects of gender and estradiol metabolism on the development and progression of PH. More recent studies are related to (1) the effects of sex and sex hormones and their metabolites on development of HFpEF and (2) the role of purine metabolism in PH with focus on hemolysis-induced pulmonary vasculopathy and PH.
 
Role purine nucleoside phosphorylase (PNPase) in development of angioproliferative vasculopathy and hemolytic angioproliferative pulmonary hypertension (HA-PH)
In sickle cell disease endothelial purine nucleoside phosphorylase (PNPase) activity stimulates angioproliferation and promotes the development of HA-PH. Further, in hemolytic states red blood cell -derived extracellular PNPase acts in concert with xanthine oxidase and guanase and the net effects of these three enzymes lead to changes in the guanosine-inosine metabolome that favor hemolytic vasculopathy and HA-PH (Figure 1).

 
 
  Figure 1


Figure 2. When superimposed on endothelial injury induced by VEGF receptor antagonist SU5416, chronic treatment with hemolyzed autologous blood (HAB) leads to development of angioproliferative PH. Occlusive [A] and plexiform (PLX) lesions [C] and neomuscularization of small-size pulmonary arteries [B] in rats treated with either Sugen 5416 (SU Day 26) or Sugen 5416+ 10 days of HAB treatment (Group SU+HAB Day 26). The combination treatment resulted in development of numerous occlusive lesions in small-size (<50?m) pulmonary arteries [A] and formation of PLX lesions [D-F] similar to those seen in Sugen+hypoxia model [G].
Figure 2
Role of estradiol metabolism in PAH. A, Activities of 2-hydroxylation, 16a-hydroxylation, and 17b-HSD pathways determine the overall biological effects of estradiol (E2) in PAH. B, In ECs, 2-methoxyestradiol (2ME) is a more potent modulator of prostacyclin, endothelin, and nitric oxide synthesis/release than (E2); 2ME and E2 have opposite effects on endothelial pathobiology in PAH (2HE, 2-hydroxyestradiol; 2ME1,2-methoxyestrone; E3, estriol; 16aE1, 16a-estrone).
Figure 3Figure 4
Rescue treatment with estradiol (day 10-21) exacerbates PH formation of occlusive and plexiform lesions in OVX female rats with SU5416+hypoxia-induced PAH. In contrast, preventive treatment with 2-ME abolishes development of angioproliferative lesions and reduces PH induced by SU5416. 
 

Journal Articles

Bilan V, Schneider F, Novelli EM, Kelley EE, Sriva S, Gladwin M, Jackson EK and Tofovic SP. EXPRESS: Experimental Intravascular Hemolysis Induces Hemodynamic and Pathological Pulmonary Hypertension - Association with Accelerated Purine Metabolism. Pulm Circ 8:2045894018791557, 2018.
Salah EM, Bastacky SI, Jackson EK and Tofovic SP. Captopril Attenuates Cardiovascular and Renal Disease in a Rat Model of Heart Failure With Preserved Ejection Fraction. J Cardiovasc Pharmacol 71:205-214, 2018.
Rafikova O, Srivastava A, Desai AA, Rafikov R and Tofovic SP. Recurrent inhibition of mitochondrial complex III induces chronic pulmonary vasoconstriction and glycolytic switch in the rat lung. Respir Res 19:69, 2018.
Goncharov DA, Goncharova EA, Tofovic SP, Hu J, Baust JJ, Pena AZ, Ray A, Rode A, Vanderpool RR, Mora AL, Gladwin MT and Lai YC. Metformin Therapy for Pulmonary Hypertension Associated with HFpEF versus PAH. Am J Respir Crit Care Med 198:681-684, 2018.
Hu J, Sharifi-Sanjani M and Tofovic SP. Nitrite Prevents Right Ventricular Failure and Remodeling Induced by Pulmonary Artery Banding. J Cardiovasc Pharmacol 69:93-100, 2017.
Tofovic SP, Salah EM, Smits GJ, Whalley ET, Ticho B, Deykin A and Jackson EK. Dual A1/A2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction. J Pharmacol Exp Ther 356:333-340, 2016.
Lai YC, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, St Croix CM, Garcia-Ocana A, Goncharova EA, Tofovic SP, Mora AL and Gladwin MT. SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction. Circulation 133:717-731, 2016.
Rafikova O, Rafikov R, Kumar S, Sharma S, Aggarwal S, Schneider F, Jonigk D, Black SM and Tofovic SP. Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonary hypertension. Free Radic Biol Med 56:28-43, 2013.
Bilan VP, Salah EM, Bastacky S, Jones HB, Mayers RM, Zinker B, Poucher SM and Tofovic SP. Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats. J Endocrinol 210:293-308, 2011.

Sponsored Research

Role of Cardiac and Renal DPP4 - 4/1/2017 - 3/31/2021
NIH - R01HL069846