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Faculty

Nilanjana Maulik
Professor of Surgery
nmaulik@neuron.uchc.edu

• Ph.D., University of Calcutta
• Cell Biology Graduate Program
• Accepting Lab Rotation Students: Summer '08, Fall '08, Spring '09
  

Areas of Interests:
Molecular and Cellular signaling during myocardial ischemia and reperfusion

(a) A remodeling process is well known to occur after myocardial infarction (MI) in experimental animals. Post-infarct remodeling denotes both favorable and unfavorable changes in the tissue. Favorable remodeling enhances recovery of regional myocardial function in the weeks after infarction in the adapted heart. Occlusion of a main coronary depletes the blood supply to the myocardium and subsequently reduces cardiac function, which ultimately leads to heart failure. Progressive, chronic coronary artery occlusion has been shown to induce development of collateral arteries to re-establish and maintain blood flow to the myocardium at risk via the growth of new capillary vessels or angiogenesis. Studies from my laboratory as well as from others have already confirmed the protective role of collaterals against myocardial ischemia and cell death. Angiogenesis is a physiologically potent process involved in growth and development and that may one day translate into a first-line approach for the treatment of chronic ischemic heart disease. The use of gene therapy and growth factors is a more natural way of inducing angiogenesis. Further understanding of the underlying biology of revascularization is needed to determine the ability of growth factors to induce functionally significant angiogenesis in patients with atherosclerotic, diabetic disease and related conditions including endothelial dysfunction, which may inhibit vessel growth.

Current research is focused on the investigation of basic molecular mechanism of myocardial angiogenesis in the ischemic heart. To develop better and more effective therapeutic strategies using the powerful concept of inducing new vessel growth by employing vascular growth factors, it is essential to further our understanding of the molecular mechanisms and chain of events underlying the fascinating process of angiogenesis. Our angiogenesis work is directed toward understanding the program for the expression of various survival and growth factors involved in coronary arteriogenesis and angiogenesis.

My laboratory is involved in studying myocardial angiogenesis and/or arteriogenesis at four different levels:

• In vitro study using human coronary arteriolar endothelial cells and cardiomyocytes
• Laboratory designed permanent LAD occlusion (survival) model in rat/mice
• At the molecular level in transgenic/knock-out mice
• At the pre-clinical level testing the ability of gene delivery and growth factor administration to ameliorate myocardial ischemia in animal models

(b) Another ongoing area of research in which I am involved and very much interested is studying the mechanism of pharmacological as well as ischemic preconditioning of the heart. During last 14 years of study, we documented the involvement of several signal transduction pathways as well as several multiple kinases including MAP kinases and protein kinase C (PKC). We also demonstrated the role of several redox-sensitive transcription factors and genes such as NFB, AP-1 and Bcl-2 in the regulation of ischemic preconditioning in ex-vivo rat/mouse models. Our laboratory was the first to show that preconditioning reduces cardiomyocyte apoptosis through the modulation of MAP kinase signaling and NFB plays an essential role in this signaling process. Our lab demonstrated that reactive oxygen species function as messenger molecules during the preconditioning. While preconditioning has now been considered as a state-of-the-art tool for myocardial protection, the application of preconditioning has been mostly limited to healthy heart model. Unfortunately, only a few studies have focused on the effect of preconditioning in the hearts with concurrent abnormalities relevant to coronary artery disease in humans. Clinical studies clearly identify a number of pathological conditions that increase mortality due to myocardial infarction and more likely to undergo open-heart surgery. These include aging, diabetes, hypertension, atherosclerosis and congestive heart failure. A very limited study has been performed on pathologic hearts, and most of the studies have shown that these hearts are difficult, if not impossible, to be preconditioned. However, none of these studies attempted to examine the mechanism(s) of protection in these hearts. We recognize that this is an important issue, and it is likely that the mechanism(s) of signal transduction process is quite different from that which is known to occur in the hearts during preconditioning. Once, the mechanism is known, we then can pinpoint the reason for failure of preconditioning these pathologic hearts.

This involves extensive investigation. Therefore we use several animal models to study this clinical aspect such as:

• We use diabetic, hypertensive and atherosclerotic rats as well as mice for experimental purpose. In ex-vivo model, hearts are subjected to ischemia (no-flow) followed by reperfusion (flow). Both Langendorff as well as working mode of heart preparation are used depending upon the parameters involved.
• We use both transgenic and knock out animals
• Survival as well as non-survival procedure is involved
• In-vitro studies are involved

Techniques Involved in our research projects:

(1) Cell culture: endothelial cells, cardiomyocytes (isolated from adult and neonatal rats and mice); (2) Ex-vivo heart model both Langendorff and working heart; (3) Survival surgery (LAD occlusion) both in rat and mouse; (4) Measurement of in vivo Hemodynamic parameter including blood flow by neutron microsphere technique; (5) RNA, DNA and Protein isolation; (6) Northern blot analysis, cloning, RNA protection assay; (7) RT-PCR, Real Time RT-PCR; (8) Western blot analysis; (9) Differential gene analysis; (10) DNA-Microarray; (11) Protein/DNA Array; (12)Bio-informatics; (13) Proteomic analysis : 2-D gel electrophoresis and Antibody Array; (14) Immuno-histochemistry; (15) Spectrophotometric analysis; (16) Enzymatic analysis; (17) HPLC Analysis;and (18) ELISA

Selected Publications:

Thirunavukkarasu M, Addya S, Juhasz B, Pant R, Zhan L, Surrey S, Maulik G, Menon VP, Maulik N. Heterozygous Disruption Of Flk-1 Receptor Leads To Myocardial Ischemia Reperfusion Injury In Mice: Application Of Affymetrix Gene Chip Analysis. J Cell Mol Med. 2008 Feb 8;

Penumathsa SV, Thirunavukkarasu M, Zhan L, Maulik G, Menon VP, Bagchi D,Maulik N. Resveratrol enhances GLUT-4 translocation to the caveolar lipid raft fractions through AMPK/AKT/eNOS signaling pathway in diabetic myocardium. J Cell Mol Med. 2008 Feb 4; [Epub ahead of print]

Maulik N, Thirunavukkarasu M. Growth factor/s and cell therapy in myocardial regeneration. J Mol Cell Cardiol. 2007 Dec 7; [Epub ahead of print]

Juhasz B, Thirunavukkarasu M, Pant R, Zhan L, Penumathsa S, Secor ER,Srivastava S, Raychaudhuri U, Menon VP, Otani H, Thrall RS, Maulik N. Bromelain induces cardioprotection against ischemia reperfusion injury through Akt/Foxo pathway in rat myocardium. Am J Physiol Heart Circ Physiol. 2008 Jan 11; [Epub ahead of print]

Penumathsa SV, Koneru S, Zhan L, John S, Menon VP, Prasad K, Maulik N. Secoisolariciresinol diglucoside induces neovascularization-mediated cardioprotection against ischemia-reperfusion injury in hypercholesterolemic myocardium. J Mol Cell Cardiol. 2008 Jan; 44(1):170-179. Epub 2007 Oct 4.

Thirunavukkarasu M, Penumathsa SV, Koneru S, Juhasz B, Zhan L, Otani H, Bagchi D, Das DK, Maulik N. Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: Role of nitric oxide, thioredoxin, and heme oxygenase. Free Radic Biol Med. 2007 Sep 1; 43(5):720-9. Epub 2007 May 10.

Thirunavukkarasu M, Juhasz B, Zhan L, Menon VP, Tosaki A, Otani H, Maulik N. VEGFR1 (Flt-1+/-) gene knockout leads to the disruption of VEGF-mediated signaling through the nitric oxide/heme oxygenase pathway in ischemic preconditioned myocardium. Free Radic Biol Med. 2007 May 15;42(10):1487-95. Epub 2007 Feb 20.

Koneru S, Penumathsa SV, Thirunavukkarasu M, Samuel SM, Zhan L, Han Z, Maulik G, Das DK, Maulik N. Redox regulation of ischemic preconditioning is mediated by the differential activation of caveolins and their association with eNOS and GLUT-4. Am J Physiol Heart Circ Physiol. 2007 May;292(5):H2060-72. Epub 2007 Feb 2.

Penumathsa SV, Thirunavukkarasu M, Koneru S, Juhasz B, Zhan L, Pant R, Menon VP, Otani H, Maulik N. Statin and resveratrol in combination induces cardioprotection against myocardialinfarction in hypercholesterolemic rat. J Mol Cell Cardiol. 2007 Mar;42(3):508-16. Epub 2006 Dec 26.

Penumathsa SV, Koneru S, Thirunavukkarasu M, Zhan L, Prasad K, Maulik N. Secoisolariciresinol diglucoside: relevance to angiogenesis and cardioprotection against ischemia-reperfusion injury. J Pharmacol Exp Ther. 2007 Feb;320(2):951-9. Epub 2006 Nov 28.

Maulik N. Reactive oxygen species drives myocardial angiogenesis? Antioxid Redox Signal. 2006 Nov-Dec;8(11-12):2161-8. Review.

Thirunavukkarasu M, Penumathsa SV, Juhasz B, Zhan L, Cordis G, Altaf E, Bagchi M, Bagchi D, Maulik N. Niacin-bound chromium enhances myocardial protection from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H820-6.

Vidavalur R, Penumathsa SV, Zhan L, Thirunavukkarasu M, Maulik N. Sildenafil induces angiogenic response in human coronary arteriolar endothelial cells through the expression of thioredoxin, hemeoxygenase and vascular endothelial growth factor. Vascul Pharmacol. 2006 Aug;45(2):91-5. Epub 2006.

Fukuda S, Kaga S, Zhan L, Bagchi D, Das DK, Bertelli A, Maulik N. Resveratrol ameliorates myocardial damage by inducing vascular endothelial growth factor-angiogenesis and tyrosine kinase receptor Flk-1. Cell Biochem Biophys. 2006;44(1):43-9.

Kaga S, Zhan L, Altaf E, Maulik N. Glycogen synthase kinase-3beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and surviving expression in rat ischemic preconditioned myocardium. J Mol Cell Cardiol. 2006 Jan;40(1):138-47. Epub 2005.

Maulik N. Effect of p38 MAP kinase on cellular events during ischemia and reperfusion possible therapy. Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2302-3.

Kaga S, Zhan L, Matsumoto M, Maulik N. Resveratrol enhances neovascularization in the infarcted rat myocardium through the induction of thioredoxin-1, heme oxygenase-1 and vascular endothelial growth factor. J Mol Cell Cardiol. 2005 Nov;39(5):813-22. Epub 2005.

Addya S, Shiroto K, Turoczi T, Zhan L, Kaga S, Fukuda S, Surrey S, Duan LJ, Fong GH, Yamamoto F, Maulik N. Ischemic preconditioning-mediated cardioprotection is disrupted in heterozygous Flt-1 (VEGFR-1) knockout mice. J Mol Cell Cardiol. 2005 Feb;38(2):345-51. Epub 2005.

Mathur P, Kaga S, Zhan L, Das DK, Maulik N. Potential candidates for ischemic preconditioning-associated vascular growth pathways revealed by antibody array. Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H3006-10. Epub 2005.

Mathur P, Kaga S, Zhan L, Das DK, Maulik N. Antibody-array technique reveals overexpression of important DNA-repair proteins during cardiac ischemic preconditioning. J Mol Cell Cardiol. 2005 ;38(1):99-102.

Fukuda S, Yoshii S, Kaga S, Matsumoto M, Kugiyama K, Maulik N. Angiogenic strategy for human ischemic heart disease: brief overview.Mol Cell Biochem. 2004 Sep;264(1-2):143-9.

Maulik N. Angiogenic signal during cardiac repair.Mol Cell Biochem. 2004 Sep;264(1-2):13-23, Review

Fukuda S, Kaga S, Sasaki H, Zhan L, Zhu L, Otani H, Kalfin R, Das DK, Maulik N. Angiogenic signal triggered by ischemic stress induces myocardial repair in rat during chronic infarction. J Mol Cell Cardiol. 2004 Apr;36(4):547-59.

Maulik N. Ischemic preconditioning mediated angiogenic response in the heart. Antioxid Redox Signal. 2004 Apr;6(2):413-21, Review.

Maulik N. Redox control of cardiac preconditioning. Antioxid Redox Signal. 2004 Apr;6(2):321-3.

rev. 2-08