Abstract

BackgroundIschemia-reperfusion (I/R) injury contributes to organ dysfunction in a variety of clinical disorders, including myocardial infarction, stroke, organ transplantation, and hemorrhagic shock. Recent investigations have demonstrated that apoptosis as an important mechanism of cell death leading to organ dysfunction following I/R. Intracellular danger-associated molecular patterns (DAMPs) released during cell death can activate cytoprotective responses by engaging receptors of the innate immune system.Methodology/Principal FindingsIschemia was induced in the mouse hind limb by tourniquet or in the heart by coronary artery ligation. Reperfusion injury of skeletal or cardiac muscle was markedly reduced by intraperitoneal or subcutaneous injection of recombinant human (rh)BCL2 protein or rhBCL2-related protein A1 (BCL2A1) (50 ng/g) given prior to ischemia or at the time of reperfusion. The cytoprotective activity of extracellular rhBCL2 or rhBCL2A1 protein was mapped to the BH4 domain, as treatment with a mutant BCL2 protein lacking the BH4 domain was not protective, whereas peptides derived from the BH4 domain of BCL2 or the BH4-like domain of BCL2A1 were. Protection by extracellular rhBCL2 or rhBCL2A1 was associated with a reduction in apoptosis in skeletal and cardiac muscle following I/R, concomitant with increased expression of endogenous mouse BCL2 (mBCL2) protein. Notably, treatment with rhBCL2A1 protein did not protect mice deficient in toll-like receptor-2 (TLR2) or the adaptor protein, myeloid differentiation factor-88 (MyD88).Conclusions/SignificanceTreatment with cytokine-like doses of rhBCL2 or rhBCL2A1 protein or BH4-domain peptides reduces apoptosis and tissue injury following I/R by a TLR2-MyD88-dependent mechanism. These findings establish a novel extracellular cytoprotective activity of BCL2 BH4-domain proteins as potent cytoprotective DAMPs.

Highlights

  • Cellular injury resulting from tissue damage induced by a variety of insults elicits host defense and repair responses

  • We show that exogenously administered recombinant human BCL2 or rhBCL2A1 protein and synthetic peptides derived from the BH4 domain of BCL2 or the BH4-like domain of BCL2-related protein A1 (BCL2A1) [6] confer protection against I/R injury of hind limb skeletal muscle or cardiac muscle

  • In order to determine whether the protection against I/R injury was restricted to BCL2, we examined the effect of rhBCL2A1, an anti-apoptotic BCL2 family member [11,12,13]

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Summary

Introduction

Cellular injury resulting from tissue damage induced by a variety of insults elicits host defense and repair responses. We show that exogenously administered recombinant human BCL2 (rhBCL2) or rhBCL2A1 protein and synthetic peptides derived from the BH4 domain of BCL2 or the BH4-like domain of BCL2A1 [6] confer protection against I/R injury of hind limb skeletal muscle or cardiac muscle. This protection was associated with increased expression of endogenous mouse BCL2 protein and reduced apoptosis in the muscle subjected to I/R injury. Intracellular dangerassociated molecular patterns (DAMPs) released during cell death can activate cytoprotective responses by engaging receptors of the innate immune system

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