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Critical role of extracellular heat shock cognate protein 70 in the myocardial inflammatory response and cardiac dysfunction after global ischemia-reperfusion. Am J Physiol Heart Circ Physiol 294: H2805-H2813, 2008. First published April 25, 2008 doi:10.1152/ajpheart.00299.2008.-Previous studies showed that Toll-like receptor 4 (TLR4) modulates the myocardial inflammatory response to ischemia-reperfusion injury, and we recently found that cytokines link TLR4 to postischemic cardiac dysfunction. Although TLR4 can be activated in cultured cells by endogenous agents including heat shock protein 70, how it is activated during myocardial ischemia-reperfusion is unknown. In the present study, we examined 1) whether heat shock cognate protein 70 (HSC70), which is constitutively expressed in the myocardium, is released during ischemia-reperfusion; 2) whether extracellular HSC70 induces the myocardial inflammatory response and modulates cardiac function; and 3) whether HSC70 exerts these effects via TLR4. We subjected isolated mouse hearts to global ischemia-reperfusion via the Langendorff technique. Immunoblotting and immunostaining detected the release of HSC70 from the myocardium during reperfusion. Treatment with an antibody specific to HSC70 suppressed myocardial cytokine expression and improved cardiac functional recovery after ischemia-reperfusion. Recombinant HSC70 induced NF-B activation and cytokine expression and depressed myocardial contractility in a TLR4-dependent manner. These effects required the substratebinding domain of HSC70. Fluorescence resonance energy transfer analysis of isolated macrophages demonstrated that extracellular HSC70 interacts with TLR4. Therefore, this study demonstrates for the first time that 1) the myocardium releases HSC70 during ischemiareperfusion, 2) extracellular HSC70 contributes to the postischemic myocardial inflammatory response and to cardiac dysfunction, 3) HSC70 exerts these effects through a TLR4-dependent mechanism, and 4) the substrate-binding domain of HSC70 is required to induce these effects. Thus extracellular HSC70 plays a critical role in regulating the myocardial innate immune response and cardiac function after ischemia-reperfusion.Toll-like receptor 4; cytokines; nuclear factor-B; messenger ribonucleic acid CARDIAC SURGERY OFTEN INVOLVES obligatory global myocardial ischemia-reperfusion, which causes a myocardial inflammatory response characterized by cytokine production (16, 18). Several proinflammatory cytokines, including TNF-␣, IL-1␤, and IL-6, contribute to myocardial injury after ischemia-reperfusion (12, 31). Preserving cardiac function after global ischemia-reperfusion therefore requires regulation of the myocardial inflammatory response. However, the signaling mechanisms underlying the myocardial inflammatory response to global ischemia-reperfusion are unclear.Previous studies implicated Toll-like receptor 4 (TLR4) signaling in the inflammatory response associated with myocardial ischemia-reperfusion injury. In mice treated with the TLR4 antagonis...

We have recently reported a series of novel synthetic technologies for the facile construction of complex polycycles, [1] diverse heterocycles, [2] amino-sugars, [3] and a,bunsaturated carbonyl compounds [4] induced by hypervalent iodine reagents (o-iodoxybenzoic acid (1-hydroxy-1,2-benziodoxol-3(1H)-one-1-oxide, IBX) and Dess ± Martin periodinate (DMP)). This spate of reactions, which arose from a discovery made during the total synthesis of the CP molecules, [5] necessitated an in-depth mechanistic investigation to gain further understanding of the sequence of processes involved. Herein we present divergent mechanistic pathways for these IBX-and DMP-mediated reactions based on isotope labeling, kinetic studies, cyclic voltammetry measurements, NMR spectroscopic analysis, and designed cascade reactions.For the IBX-mediated ring closures of anilides and related systems to N-heterocycles, we had previously proposed a pathway predicated on single electron transfer (SET) as shown in Scheme 1 (I 3II 3III 3IV 3V). [3] To confirm this Scheme 1. Proposed mechanism of the IBX-mediated ring closure of anilides and related systems to N-heterocycles (I 3V). SET single electron transfer, IBX o-iodoxybenzoic acid.

Background-Although Toll-like receptor 4 (TLR4) has been implicated in the myocardial injury caused by regional ischemia/reperfusion, its role in the myocardial inflammatory response and in contractile dysfunction after global ischemia/reperfusion is unclear. Cytokines, particularly tumor necrosis factor-α (TNF-α), contribute to the mechanism of myocardial dysfunction after global ischemia/reperfusion. We hypothesized that a TLR4-mediated cytokine cascade modulates myocardial contractile function after global ischemia/reperfusion. This study examined whether TLR4 regulates TNF-α and interleukin (IL)-1β peptide production during global ischemia/ reperfusion and whether TLR4 signaling influences postischemic cardiac function through TNF-α and IL-1β.

Cardiac surgery with global myocardial ischemia-reperfusion (I/R) induces a myocardial inflammatory response that impairs cardiac recovery. Chemokines contribute to the overall myocardial inflammatory response through inducing leukocyte infiltration. Although Toll-like receptor 4 (TLR4) has an important role in postischemic myocardial injury, the relative roles of myocardial tissue and leukocyte TLR4 in leukocyte infiltration, as well as the role of TLR4 in myocardial chemokine expression, are unclear. Our recent study, in an isolated mouse heart model of global I/R, found that the 70-kDa heat shock cognate protein (HSC70) is released from cardiac cells and mediates the expression of cardiodepressant cytokines via a TLR4-dependent mechanism. In the present study, we tested the hypotheses that myocardial tissue TLR4 has a major role in mediating neutrophil infiltration and that myocardial TLR4 and extracellular HSC70 contribute to the mechanisms underlying cardiac chemokine response to global I/R. We subjected hearts isolated from TLR4-defective and TLR4-competent mice to global I/R and examined myocardial neutrophil infiltration and expression of keratinocyte-derived chemokine (KC) and monocyte chemoattractant protein-1 (MCP-1). TLR4-defective hearts exhibited reduced neutrophil infiltration regardless of the phenotypes of neutrophils perfused during reperfusion and expressed lower levels of KC and MCP-1. HSC70-specific antibody reduced myocardial expression of KC and MCP-1 after I/R. Furthermore, perfusion of HSC70 increased KC and MCP-1 expression in TLR4-competent hearts but not in TLR4-defective hearts, and HSC70 also induced the chemokine response in macrophages in a TLR4-dependent fashion. A recombinant HSC70 fragment lacking the substrate-binding domain was insufficient to induce chemokine expression in hearts and cells. This study demonstrates that myocardial tissue TLR4, rather than neutrophil TLR4, is the determinant of myocardial neutrophil infiltration after global I/R. TLR4 mediates myocardial chemokine expression, and the mechanisms involve extracellular HSC70. These results imply the HSC70-TLR4 interaction as a novel mechanism underlying the myocardial chemokine response to global I/R.

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Syntheses of the three key building blocks (65, 98, and 100) required for the total synthesis of the proposed structure of azaspiracid-1 (1a) are described. Key steps include a TMSOTf-induced ring-closing cascade to form the ABC rings of tetracycle 65, a neodymium-catalyzed internal aminal formation for the construction of intermediate 98, and a Nozaki-Hiyama-Kishi coupling to assemble the required carbon chain of fragment 100. The synthesized fragments, obtained stereoselectively in both their enantiomeric forms, were expected to allow for the construction of all four stereoisomers proposed as possible structures of azaspiracid-1 (1a-d), thus allowing the determination of both the relative and absolute stereochemistry of the natural product.

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