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Cardiovascular Research Laboratory
Bysani Chadrasekar

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Faculty:

Bysani Chandrasekar, DVM, PhD

Postdoctoral Fellows:
Siddesha Jalahalli
Siva Sankara (Prasad) Sakamuri

Current, Major Projects:

NIH R01HL086787 (NHLBI)- THE ROLE OF INTERLEUKIN-18 IN MYOCARDIAL HYPERTROPHY AND FAILURE

Myocardial hypertrophy and its transition to failure remains a significant cause of morbidity and mortality. Sustained production of inflammatory cytokines is a hallmark of all phases of this transition. In particular, interleukin (IL)-18 is upregulated in heart failure, which directly correlates with the severity of myocardial damage and dysfunction, and poor clinical outcome in heart failure. Our preliminary studies demonstrate that IL-18 induces cardiomyocyte hypertrophy and fibroblast migration and proliferation in vitro, suggesting potential pro-hypertrophic and pro-fibrotic roles for IL-18 in vivo. Our studies in wild-type mice show that pressure overload induced by transverse aortic constriction (TAC) leads to left ventricular hypertrophy (LVH) and increased IL-18 expression. Remarkably, this hypertrophy can be significantly reduced by IL-18 neutralizing antibodies. IL-18 knockout mice develop significantly less LVH in response to TAC; conversely, cardiac-specific overexpression of IL-18 induces LVH and heart failure in the absence of TAC. Rabbit models also exhibit LVH and increased IL-18 expression in response to TAC. Furthermore, our preliminary human studies clearly demonstrate the prognostic power of systemic IL-18 levels to predict cardiac failure. Thus, our central HYPOTHESIS is that IL-18 is a key mediator of LVH and failure that results in pathological remodeling through the induction of hypertrophy-associated kinases, fetal genes, growth factors, and matrix metalloproteinases. To address this HYPOTHESIS, we will investigate IL-18-dependent signaling in cardiomyocytes in vitro (Specific Aim 1), the molecular mechanisms involved in IL-18-mediated cardiac fibroblast migration and proliferation in vitro (Specific Aim 2), and the causal role of IL-18 in LVH, fibrosis and failure in vivo, using cardiac-restricted IL-18KO and cardiac-specific IL-18 transgenic mice (Specific Aim 3). Results obtained in mice will be validated in a rabbit model of pressure-overload hypertrophy and failure. Systemic IL-18 levels will be measured and correlated with the relative severity of cardiac hypertrophy and failure in humans. Collectively, these proposed studies will establish IL-18 as a potentially use therapeutic target to attenuate the progression of LVH to cardiac failure. PUBLIC HEALTH RELEVANCE: t Narrative Myocardial hypertrophy and its transition to congestive heart failure are important diseases, resulting in quarter million deaths and one million hospitalizations annually in the US. Understanding the molecular mechanisms underlying these pathological processes will help us design more effective therapeutic strategies to better care for these patients. The primary goal of this proposal is to better understand the role of inflammatory cytokines, interleukin-18 in particular, in myocardial hypertrophy and its transition to failure.

7I01BX000246-02 (VETERANS AFFAIRS)- INTERLEUKIN-18 AND POST INFARCT MYOCARDIAL REMODELING

Acute myocardial infarction (MI) is a major cause of morbidity and mortality in the US, within both the military veteran and civilian populations. Post-infarct myocardial remodeling, hypertrophy and its transition to congestive heart failure are important diseases, resulting in quarter million deaths and one million hospitalizations annually in the US. Understanding the molecular mechanisms underlying these pathological processes will help us design more effective therapeutic strategies to better care for these patients. The primary goal of this proposal is to better understand the role of inflammatory cytokines, interleukin-18 in particular, in post-infarct myocardial injury, remodeling and failure.


Recent Publications:

  1. Shanmugam P, Valente AJ, Prabhu SD, Venkatesan B, Yoshida T, Delafontaine P, Chandrasekar B. Angiotensin-II type 1 receptor and NOX2 mediate TCF/LEF and CREB dependent WISP1 induction and cardiomyocyte hypertrophy. J Mol Cell Cardiol. 2011. PMID 21376054.
  2. Reddy VS, Valente AJ, Delafontaine P, Chandrasekar B. Interleukin-18/WNT1-Inducible signaling pathway protein-1 signaling mediates human saphenous vein smooth muscle cell proliferation. J Cell Physiol. 2011. PMID 21321938.
  3. Reddy VS, Prabhu SD, Mummidi S, Valente AJ, Venkatesan B, Shanmugam P, Delafontaine P, Chandrasekar B. Interleukin-18 induces EMMPRIN expression in primary cardiomyocytes via JNK/Sp1 signaling and MMP-9 in part via EMMPRIN and through AP-1 and NF-kappaB activation. Am J Physiol Heart Circ Physiol. 2010;299(4):H1242-54. PMID 20693392, PMCID: 2957343.
  4. Venkatesan B, Valente AJ, Prabhu SD, Shanmugam P, Delafontaine P, Chandrasekar B. EMMPRIN activates multiple transcription factors in cardiomyocytes, and induces interleukin-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-kappaB andMKK7/JNK/AP-1 signaling. J Mol Cell Cardiol. 2010;49(4):655-63. PMID 20538003, PMCID: 3042694.
  5. Schallhorn RA, Patel DN, Chandrasekar B, Mealey BL. Periodontal disease in association with systemic levels of interleukin-18 and CXC ligand 16 in patients undergoing cardiac catheterization. J Periodontol. 2010;81(8):1180-6. PMID 20476884.
  6. Halade GV, Rahman MM, Bhattacharya A, Barnes JL, Chandrasekar B, Fernandes G. Docosahexaenoic acid-enriched fish oil attenuates kidney disease and prolongs median and maximal life span of autoimmune lupus-prone mice. J Immunol. 2010;184(9):5280-6. PMID 20368275, PMCID: 2952419.
  7. Venkatesan B, Prabhu SD, Venkatachalam K, Mummidi S, Valente AJ, Clark RA, Delafontaine P, Chandrasekar B. WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death. Cell Signal. 2010;22(5):809-20. PMID 20074638, PMCID: 2885703.

 

 

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