Department of Molecular Cardiology
Olga Stenina Adognravi, Ph.D.
Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
Phone: (216) 444-9057
Fax: (216) 445-8204
Vascular complications of diabetes are the main and a long-standing interest of my group. Hyperglycemia is an independent risk-factor for development of macrovascular and microvascular complications. High blood glucose regulates the expression of a number of vascular genes implicated in atherogenesis, angiogenesis, and endothelial dysfunction. Our goal is to identify the molecular pathways activated in response to high glucose and leading to abnormal expression of vascular genes.
Recently, we have identified two novel molecular pathways controlled by glucose in endothelial cells:
1. Glucose regulates the activity of Aryl Hydrocarbon Receptor (Ahr), a nuclear receptor for multiple xenobiotic compounds that has been associated with cardiovascular disease and diabetes in epidemiological studies and in animals. Ahr controls the transcription of vascular genes associated with protection from the oxidative stress, and abnormal angiogenesis and atherogenesis.
2. The pathological changes of vasculature in diabetes are tissue- and organ-specific: angiogenesis can be dramatically upregulated in one tissue/organ (retinal neovascularization) and dramatically suppressed in another tissue/organ (e.g., skin, heart). We have identified a novel tissue-specific molecular mechanism that provides explanation for the aberrant angiogenesis. Hyperglycemia upregulates the expression of miR-467 in a tissue-specific manner. miR-467 binds to the untranslated region of thrombospondin-1 (TSP-1) mRNA and inhibits TSP-1 protein synthesis. The descreased production of TSP-1, a potent anti-angiogenic protein, results in upregulation of angiogenesis in selected tissues where this mechanism is present. miR-467 is expressed in a tissue-specific manner in cancer cells and may provide an explanation for the associations of diabetes and cancer.
In other words ...
Despite the recent advances in the treatment of diabetes, the precise control of blood glucose remains problematic. Hyperglycemia (high blood glucose) is an independent risk factor for the development of vascular complications of diabetes, which are the main cause of morbidity and mortality in diabetic patients. Pathological changes of vasculature develop in most diabetic patients with type 1 and type 2 diabetes and manifest as atherosclerotic lesions in large arteries or altered vascularization of organs causing abnormal function of these organs (retinopathy, nephropathy, neuropathy, cardiomyopathy). The molecular mechanisms activated in vascular cells by high blood glucose and resulting in pathological changes of the vasculature remain largely unknown. The intracellular molecular mechanisms that regulate vascular gene expression in response to hyperglycemia are our focus. We are examining the intracellular pathways activated by high blood glucose and controlling gene transcription and protein production and, as a result, the development of atherosclerotic lesions in large arteries and the growth of new microvessels in tissues and organs. Extracellular matrix (ECM) undergoes the most profound changes in diabetic vasculature: the amount of ECM and its composition change dramatically. To understand the role of blood glucose in these changes, we study the pathways controlling production of thrombospondins, ECM proteins known to regulate the growth of new vessels (angiogenesis) and the development of atherosclerotic lesions. As a result of this work, we have identified new and promising potential therapeutic targets that may facilitate prevention and treatment of diabetic vascular complications and reduce the socio-economic burden of diabetes.
1. Dolgov V.V., Preobrazhensky S.N., Stenina O.I., Bondarenko M.F., Repin V.S. (1982) The quantitative analysis of LDL interaction with perfused rabbit aorta. Bull. Exp. Biol. Med. (russ) 10:122-124
2. Voyno-Yassenetskaya T.A., Stenina O.I., Repin V.S., Skuratovskaya L.N., Guliaeva R.V., Kryzhanovsky G.N. (1988) Receptor-dependent injury to the perfused rabbit and human aorta. Bulleten of Academy of Medical Science of USSR (russ) 2:89-93
3. Kondakov I.K., Voyno-Yassenetskaya T.A., Stenina O.I., Repin V.S. (1988) The comparative ultrastructural characteristic of endothelial injuries produced by catecholamines using scanning and transmission electron microscopy (1988) Aichive of Pathology (russ)
4. Stenina O.I., Voyno-Yassenetskaya T.A., Menshikov G.B.,Repin V.S. (1988) An agonist of beta-adrenergic receptors isoproterenol enhances angiotensin II-dependent injury of rabbit aortic endothelium. Bull. Exp. Biol. Med. (russ) 10: 433-436
5. Stenina O.I., Voyno-Yassenetskaya T.A., Bobryshev Yu. V.,Repin V.S., Aiken J.W. (1988). Massive deendothelialization in rabbit and human aorta mediated by simultaneous application of the stable analog of thromboxane A2 U44,069 and beta-adrenoreceptor agonist isoproterenol. Cardiovascular World Report 1(1): 60-67
6. Stenina O.I., Zacharova O.S., Bobryshev Yu. V.,Repin V.S. (1989) Endothelial injuries: the role in the vessel pathology (review). In: Sums of the science and technics. Human and animal physiology (russ) 38:89-133, VINITI, Moscow
7. Stenina O.I., Baldenkov G.N., Tkachuk V.A.,Repin V.S.(1989) Ca2+-channel blockers prevent receptor-mediated endothelial damage in the perfused rabbit aorta. J. Mol.Cell Cardiol. 21:S20
8. Stenina O.I., Baldenkov G.N., Tkachuk V.A.,Repin V.S.(1989) Nitroglycerol prevents receptor-mediated massive deendothelialization in the perfused rabbit aorta. J. Mol.Cell Cardiol. 21:S20
9. Babaev V.R., Bobryshev Yu. V., Stenina O.I., Tararak E.M., Gabbiani G. (1990) Heterogeneity of smooth muscle cells in atheromatous plaque of human aorta. Am.J.Pathol. 136(5):1031-42
10. Babaev V.R., Bobryshev Yu. V., Stenina O.I., Tararak E.M. (1990) Phenotypic variants of the smooth muscle cells in an atheromatous plaque of the human aorta. Archive of Pathology (russ) 52(5): 16-21
11. Olga I. Stenina, Earl J. Poptic, and Paul E. DiCorleto (2000) Thrombin activates a Y box-binding protein (DNA-binding protein B) in endothelial cells. J Clin Invest, 106(4): 579-587
12. Olga I. Stenina, Kristin M. Shaneyfelt and Paul E. DiCorleto(2001) Thrombin induces the release of the Y-box protein dpbB from mRNA: a new mode of transcription factor activation. Proc. Natl. Acad. Sci., 98(13): 7277-7282
13. Stenina O., Pudota B. N., McNally B. A., Hommema E. L., Berkner K. L. (2001) Tethered processivity of the vitamin K-dependent carboxylase: factor IX is efficiently modified in a mechanism which distinguishes gla's from glu's and which accounts for comprehensive carboxylation in vivo. Biochemistry 40:10301-10309
14. Topol EJ, McCarthy J, Gabriel S, Moliterno DJ, Rogers WJ, Newby LK, Freedman M, Metivier J, Cannata R, O'Donnell CJ, Kottke-Marchant K, Murugesan G, Plow EF, Stenina O, Daley GQ. (2001) Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation 104: 2641 -2644
15. Olga I. Stenina, Irene Krukovets, Kai Wang, Farhad Farudi, Zhongmin Zhou, Marc Penn, Eric J. Topol and Edward F. Plow (2003). The increased expression of thrombospondin-1 in the vessel wall of diabetic Zucker rat. Circulation,107:3209-3215.
16. Olga I. Stenina, Shailesh Desai, Irene Krukovets, Kelly Kight, Damir Janigro, Eric J. Topol and Edward F. Plow (2003). Expression of thrombospondin-4 by endothelial cells and differential effect of thrombospondin variants on function of endothelial cells. Circulation, 108:1514-1519.
17. Olga I. Stenina*, (2003) Regulation of gene expression in vascular cells by coagulation proteins (review). Current Drug Targets 4: 143-158.
18. Olga I. Stenina, Tatiana V. Byzova, Josephine C. Adams, Jeanette J. McCarthy, Eric J. Topol and Edward F. Plow (2004). Coronary Artery Disease and the Thrombospondin Single Nucleotide Polymorphisms (review). International Journal of Biochemistry and Cell Biology, special issue “Modulatory Adhesion Molecules in Tissue Homeostasis” (ed. J. Adams), 36: 1013-1030.
19. Olga I. Stenina* (2005). Regulation of vascular genes by glucose (review). Current Pharmaceutical Design 11 (18) : 2367-2381.
20. Olga I. Stenina and Edward F. Plow (2005). Cancer, Thrombosis and the MET Oncogene: Old Mystery, New Insights (News and Views). Nature Medicine, 11: 4-5.
22. Olga I. Stenina*, Valentin Ustinov, Irene Krukovets, Tina Marinic, Eric J. Topol and Edward F. Plow (2005). Polymorphisms A387P in Thrombospondin-4 and N700S in Thrombospondin-1 Perturb Calcium Binding Sites. FASEB Journal, 19: 1893.
23. Elzbieta Pluskota, Olga I. Stenina, Irene Krukovets, Dorota Szpak, Edward F. Plow (2005).“Differential effect of A387 and P387 Thrombospondin-4 variants on Human Neutrophils”, Blood, 106:3970.
24. Raman P., Krukovets I., Marinic T., Bornstein P., Stenina O.I.* (2007) “Glycosylation mediates effect of high glucose on thrombospondin-1 expression in vascular smooth muscle cells“, J. Biol. Chem., 282:5704-5714
25. Olga I. Stenina, Eric J. Topol, and Edward F. Plow (2007) “The Thrombospondins, Their Polymorphisms and Cardiovascular Disease”, Arteriosclerosis Thrombosis and Vascular Biology, 2007 Sep;27(9):1886-94
26. Olga I. Stenina and Edward F. Plow (2008) Counterbalancing forces: what is thrombospondin-1 doing in atherosclerotic lesions? Circulation Research 103:1053.
27. Sanghamitra Bhattacharyya, Tina E. Marinic, Irene Krukovets, George Hoppe and Olga I. Stenina*(2008) “Cell-type-specific post-transcriptional regulation of production of a potent antiangiogenic and proatherogenic protein thrombospondin-1 by high glucose” J. Biol. Chem. 283:5699-707.
28. Pankaj Dabir, Tina E. Marinic, Irene Krukovets and Olga I. Stenina* (2008) Aryl Hydrocarbon Receptor (AhR) is Activated by Glucose and Regulates the Thrombospondin-1 Gene Promoter in Endothelial Cells, Circulation Research,102:1558-65.
29. Ella Frolova, Irene Krukovets, Elzbieta Pluskota, Tim Burke, Carla Drumm, Jonathan Smith, Lauren Blech, Maria Febbraio, Paul Bornstein, Edward F. Plow and Olga I. Stenina* (2010) “Thrombospondin-4 regulates vascular imflammation and atherogenesis”, Circulation Research 107:1313
30. Priya Raman, Christy Harry, Malory Weber, Irene Krukovets and Olga I. Stenina*“A Novel Transcriptional Mechanism of Cell-Type-Specific Regulation of Vascular Gene Expression by Glucose” (2011) Arteriosclerosis Thrombosis and Vascular Biology 31:634-42.
31. Ella G. Frolova, Nikolai Sopko, Lauren Blech, Zoran B. Popović, Jianbo Li, Amit Vasanji, Carla Drumm, Irene Krukovets, Mukesh K. Jain, Marc S. Penn, Edward F. Plow,Olga I. Stenina* “Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload” (2012) FASEB J, 26:2363.
32. Raquel Bienes, Mónica Feijoo-Cuaresma, Gloria Mateo, Olga Stenina, Benilde Jiménez and María J. Calzada “Autocrine stimulation of clear-cell renal carcinoma cell migration in hypoxia via HIF-independent suppression of thrombospondin-1” Scientific Reports 2012, 2: 788
33. Sanghamitra Bhattacharyya, Kristina Sul, Irene Krukovets, Jianbo Li and Olga Stenina Adognarvi* “A novel tissue-specific mechanism of regulation of angiogenesis and cancer growth in response to hyperglycemia”, J Am Heart Assoc (2012), 1:e005967
34. Ella G. Frolova, Judith Drazba, Irene Krukovets, Volodymyr Kostenko, Lauren Blech, Christy Harry, Amit Vasanji, Carla Drumm, Pavel Sul, Guido J. Jenniskens, Edward F. Plow and Olga Stenina-Adognravi* “Control of Organization and Function of Muscle and Tendon by Thrombospondin-4.” (2014) Matrix Biology 37:35-48
35. Irene Krukovets, Matthew Legerski, Pavel Sul, and Olga Stenina-Adognravi* “Inhibition of hyperglycemia-induced angiogenesis and breast cancer growth by systemic injections of microRNA-467 antagonist” FASEB J. 2015 Sep;29(9):3726-36.
36. Santoshi Muppala, Ph.D., Irene Krukovets M.S., Ella Frolova, Ph.D., Roy Xiao, B.S., Edward Plow, Ph.D., and Olga Stenina-Adognravi, Ph.D.* “Pro-angiogenic properties of thrombospondin-4” Arterioscler Thromb Vasc Biol. 2015 Sep;35(9):1975-86.
37. Andra E. Duncan, M.D., Babak Kateby Kashy, M.D., Sheryar Sarwar, M.D., Akhil Singh, M.D., Olga Stenina-Adognravi, Ph. D., Steffen Christoffersen, Andrej Alfirevic, M.D.,Shiva Sale, M.D., Dongsheng Yang, M.S., James D. Thomas, M.D., Marc Gillinov, M.D., Daniel I. Sessler, M.D.“Hyperinsulinemic Normoglycemia Does Not Meaningfully Improve Myocardial Performance during Cardiac Surgery: A Randomized Trial” Anesthesiology, 2015 Aug;123(2):272-87.
38. Santoshi Muppala, Ph.D., Roy Xiao, B.A., Irene Krukovets, M.S., Dmitry Verbovetsky, M.D., Revanth Yendamuri, B.S., Nayab Habib, Priya Raman, Ph.D., Edward Plow, Ph.D., and Olga Stenina-Adognravi, Ph.D. “Thrombospondin-4 mediates TGF-b-induced angiogenesis”, in press, Oncogene 2017.