Abstract
Cardiac myocytes have multiple cell autonomous mechanisms that facilitate stabilization and repair of damaged sarcolemmal membranes following myocardial injury. Dysferlin is a protein which facilitates membrane repair by promoting membrane resealing. Although prior studies have shown that dysferlin-deficient (Dysf−/−) mouse hearts have an impaired recovery from acute ischemia/reperfusion (I/R) injury ex vivo, the role of dysferlin in mediating the recovery from myocardial injury in vivo is unknown. Here we show that Dysf−/− mice develop adverse LV remodeling following I/R injury secondary to the collateral damage from sustained myocardial inflammation within the infarct zone. Backcrossing Dysf−/− mice with mice lacking signaling through the Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein (Tirap−/−), attenuated inflammation and abrogated adverse LV remodeling following I/R injury. Subsequent studies using Poloxamer 188 (P188), a membrane resealing reagent, demonstrated that P188 did not attenuate inflammation nor prevent adverse LV remodeling in Dysf−/− mice following I/R injury. Viewed together these studies reveal a previously unappreciated role for the importance of membrane sealing and the resolution of inflammation following myocardial injury.
Highlights
Cardiac myocytes have multiple cell autonomous mechanisms that facilitate stabilization and repair of damaged sarcolemmal membranes following myocardial injury
We have shown previously that tumor necrosis factor (TNF), a pro-inflammatory cytokine released by cardiac myocytes and immune cells in response to ischemic tissue injury, confers cytoprotective responses in the heart that are mediated, at least in part, through the upregulation of an emergency response gene termed d ysferlin[6,7,8], that has been implicated in mediating rapid membrane repair through its ability to direct intracellular vesicles to sites of membrane injury[9]
left ventricular (LV) end-diastolic volume (EDV) (Fig. 1B) (p < 0.001 at 2 and 4 weeks of reperfusion), end-systolic volume (ESV) (Fig. 1C) (p = 0.003 at 2 weeks and p = 0.004 at 4 weeks of reperfusion), and LV mass (LVM) (p = 0.008 at 2 weeks, p < 0.001 at 4 weeks) were significantly increased in Dysf−/− hearts compared to WT (Supplemental Figure S1), whereas the LV ejection fraction (LVEF) was significantly decreased (p < 0.001 at both 2 and 4 weeks) in the Dysf−/− hearts
Summary
Cardiac myocytes have multiple cell autonomous mechanisms that facilitate stabilization and repair of damaged sarcolemmal membranes following myocardial injury. We have shown previously that tumor necrosis factor (TNF), a pro-inflammatory cytokine released by cardiac myocytes and immune cells in response to ischemic tissue injury, confers cytoprotective responses in the heart that are mediated, at least in part, through the upregulation of an emergency response gene termed d ysferlin[6,7,8], that has been implicated in mediating rapid membrane repair through its ability to direct intracellular vesicles to sites of membrane injury[9] Prior studies from this and other laboratories have shown that hearts from dysferlin-deficient mice have an impaired ability to recover from acute ischemia/reperfusion (I/R) injury ex vivo[8,10]. We show that mice lacking dysferlin (Dysf−/− mice) undergo adverse LV cardiac remodeling following I/R injury secondary to increased myocardial inflammation that is mediated by Toll-Interleukin 1 Receptor (TIR) Domain-Containing Adaptor Protein (TIRAP) signaling in the heart
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