Ischemia reperfusion injury provokes adverse left ventricular remodeling in dysferlin-deficient hearts through a pathway that involves TIRAP dependent signaling

Sarah Evans, Carla J. Weinheimer, Attila Kovacs, Jesse W. Williams, Gwendalyn J. Randolph, Wenlong Jiang, Philip M. Barger, Douglas L. Mann

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number14129
JournalScientific reports
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2020

Bibliographical note

Funding Information:
The authors would like thank Ron Dolle and the Center for Drug Discovery at Washington University for providing us FITC-labeled P188. The authors would also like to thank Lora Staloch and Jianyang Luo for their technical assistance. We would like to acknowledge the DDRCC Administrative and Resource Access Core (Grant #P30DK052574, AITAC Core) for their assistance with the trichrome staining and the Mouse Cardiovascular Phenotyping Core (MCPC) for their assistance with the closed-chest I/R experiments. This grant was supported by NIH R01 HL 111094 (DLM). JWW was supported by NIH R00 HL138163.

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