Acute myocardial infarction (MI) is a major cause of morbidity and mortality in the US, within both the veteran and civilian populations. Proinflammatory cytokines are known to play a central role in post-MI tissue injury, remodeling and failure. Interleukin-18 (IL-18) is an inducible proinflammatory cytokine, and amplifies many autoimmune and inflammatory responses via the induction of other cytokines, chemokines, and adhesion molecules. Our studies, both published and preliminary, clearly indicate that IL-18 participates in pathological remodeling post-MI. Based on these findings, our central hypothesis is that IL-18 plays a pivotal role in myocardial remodeling post-MI by promoting cardiomyocyte apoptosis and hypertrophy, by regulating the deposition and composition of extracellular matrix, and by inducing fibroblast proliferation and fibrosis. While our long-term objective is to delineate the precise pathological role of proinflammatory cytokines in myocardial remodeling, our immediate goal is to establish an etiological role for IL-18 in post-MI cardiac remodeling and failure. To address our central hypothesis, three specific aims are proposed:
In Specific Aim 1, we will define the causal role of IL-18 in vivo in post-infarct cardiac remodeling and failure using wild-type, cardiac-specific IL-18 knockout, and cardiac-restricted overexpressor (IL-18 transgenic) mice.
In Specific Aim 2, we will characterize the effects of IL-18 on cell death and hypertrophy in cardiomyocytes in vitro.
In Specific Aim 3, we will identify the IL-18-dependent molecular mechanisms responsible for migration and proliferation of cardiac fibroblast in vitro. These novel and innovative studies will integrate functional, molecular, biochemical and histological approaches in order to address the central hypothesis. Our proposed in vitro studies in cardiomyocytes and cardiac fibroblasts will help refine and further support our in vivo studies by delineating the molecular mechanisms that connect IL-18 signaling to this maladaptive phenotype. Completion of our proposed studies will provide a better understanding of the pathobiological processes involved in myocardial injury and remodeling post-MI, establish IL-18 as a causative factor, and thus identify it as a potential therapeutic target in post-MI cardiac injury and remodeling.
Narrative 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.
|Siddesha, Jalahalli M; Valente, Anthony J; Sakamuri, Siva S V P et al. (2014) Acetylsalicylic acid inhibits IL-18-induced cardiac fibroblast migration through the induction of RECK. J Cell Physiol 229:845-55|
|Siddesha, Jalahalli M; Valente, Anthony J; Yoshida, Tadashi et al. (2014) Docosahexaenoic acid reverses angiotensin II-induced RECK suppression and cardiac fibroblast migration. Cell Signal 26:933-41|
|Valente, Anthony J; Sakamuri, Siva S V P; Siddesha, Jalahalli M et al. (2013) TRAF3IP2 mediates interleukin-18-induced cardiac fibroblast migration and differentiation. Cell Signal 25:2176-84|
|Venkatesan, Balachandar; Valente, Anthony J; Das, Nitin A et al. (2013) CIKS (Act1 or TRAF3IP2) mediates high glucose-induced endothelial dysfunction. Cell Signal 25:359-71|
|Valente, Anthony J; Yoshida, Tadashi; Izadpanah, Reza et al. (2013) Interleukin-18 enhances IL-18R/Nox1 binding, and mediates TRAF3IP2-dependent smooth muscle cell migration. Inhibition by simvastatin. Cell Signal 25:1447-56|
|Valente, Anthony J; Yoshida, Tadashi; Gardner, Jason D et al. (2012) Interleukin-17A stimulates cardiac fibroblast proliferation and migration via negative regulation of the dual-specificity phosphatase MKP-1/DUSP-1. Cell Signal 24:560-8|
|Valente, Anthony J; Clark, Robert A; Siddesha, Jalahalli M et al. (2012) CIKS (Act1 or TRAF3IP2) mediates Angiotensin-II-induced Interleukin-18 expression, and Nox2-dependent cardiomyocyte hypertrophy. J Mol Cell Cardiol 53:113-24|
|Murray, David R; Mummidi, Srinivas; Valente, Anthony J et al. (2012) ?2 adrenergic activation induces the expression of IL-18 binding protein, a potent inhibitor of isoproterenol induced cardiomyocyte hypertrophy in vitro and myocardial hypertrophy in vivo. J Mol Cell Cardiol 52:206-18|
|Shanmugam, Prakashsrinivasan; Valente, Anthony J; Prabhu, Sumanth D et al. (2011) Angiotensin-II type 1 receptor and NOX2 mediate TCF/LEF and CREB dependent WISP1 induction and cardiomyocyte hypertrophy. J Mol Cell Cardiol 50:928-38|
|Reddy, Venkatapuram Seenu; Valente, Anthony J; Delafontaine, Patrice et al. (2011) Interleukin-18/WNT1-inducible signaling pathway protein-1 signaling mediates human saphenous vein smooth muscle cell proliferation. J Cell Physiol 226:3303-15|