Areas of Interest
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 NFB, 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 NFB 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.
Revised February, 2008. |
