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J. Biol. Chem., Vol. 280, Issue 23, 21997-22005, June 10, 2005

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Lipopolysaccharide Improves Cardiomyocyte Survival and Function after Serum Deprivation^*

Wei Chao, Yan Shen, Xinsheng Zhu, Huailong Zhao, Mikhail Novikov¶, Ulrich Schmidt, and Anthony Rosenzweig¶

From the Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and ^¶Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129

Toll-like receptor-4 (TLR4) and its signaling molecule interleukin-1 receptor-associated kinase (IRAK-1) play an important role in host defense and tissue inflammation. Intriguingly, systemic administration of lipopolysaccharide (LPS), the agonist for TLR4, confers a cardio-protective effect against ischemic injury. However, the mechanisms leading to the cardiac protection remain largely unknown. The present study was designed to investigate the role of TLR4 activation by LPS in protecting cardiomyocytes (CM) against apoptosis in an in vitro model of ischemia and to explore the downstream mechanisms leading to the protective effect. Incubation with LPS led to activation of IRAK-1 and protected CMs against serum deprivation (SD)-induced apoptosis as demonstrated by DNA laddering, histone-DNA fragment enzyme-linked immunosorbent assay, and activation of caspase-3. Phosphatidylinositol 3-kinase/Akt, extracellular signal-regulated kinase 1/2, and IB kinase appear to contribute to the anti-apoptotic effect of LPS since the specific inhibitors, wortmannin, PD98059, and dominant negative IKK transgene expression reversed the LPS effect. To assess whether LPS improves CM function, we examined intracellular Ca²⁺ transients and cell shortening in single adult rat CMs. SD for 6 h dramatically inhibited Ca²⁺ transients and CM contractility. LPS at 500 ng/ml significantly improved the [Ca²⁺]_i transients and enhanced contractility in control CMs as well as in CMs subjected to SD. Importantly, transient ischemia led to rapid activation of IRAK-1 in cultured CMs and in adult rat myocardium. Adenovirus-mediated transgene expression of IRAK-1 but not its kinase-deficient mutant IRAK-1(K239S) protected CMs against SD-induced apoptosis. Taken together, these data suggest an important role of TLR4 signaling via IRAK-1 in protecting against SD-induced apoptosis.

Received for publication, December 6, 2004 , and in revised form, March 7, 2005.

^* This work was supported in part by National Institutes of Health Grants HL-04336 (to W. C.) and HL-61557 (to A. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Anesthesia and Critical Care, Massachusetts General Hospital, Jackson 4, Rm. 462, 55 Fruit St., Boston, MA 02114. Tel.: 617-724-3267; Fax: 617-726-7536; E-mail: wchao{at}partners.org.

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