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Excessive βeta‐adrenergic receptor stimulation induces cardiomyocyte necroptosis via a RIP3‐dependent pathway
Author(s) -
Wu Penglong,
Wang Yibin,
Wang Xuejun
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.616.6
Subject(s) - necroptosis , programmed cell death , necrosis , knockout mouse , receptor , microbiology and biotechnology , medicine , endocrinology , apoptosis , biology , biochemistry
Background/Hypothesis Excessive β‐adrenergic receptor activation causes maladaptive cardiac remodeling in humans with myocardial infarction. Cardiomyocyte apoptosis and necrosis are both considered as the main modes of cell death in β‐adrenergic receptor agonist isoproterenol (ISO)‐induced myocardial injury but the mechanism underlying necrosis remains elusive. Necroptosis is a newly discovered form of regulated cell death that exhibits morphological characteristics of necrosis but is regulated by the receptor interacting protein kinase (RIP) 3‐dependant pathway. Necroptosis has been suggested to play a role in the pathogenesis of common cardiovascular diseases. During necroptosis, the formation of necroptosomes consisting of proteins including RIP3 and RIP1 is critical. More recently, Ca 2+ /calmodulin‐dependent kinase II (CaMKII), which can be phosphorylated and thereby activated by β‐adrenergic receptor activation, was also reported to be involved in cardiomyocyte necroptosis by directly binding to and being phosphorylated by RIP3. However, whether ISO‐induced cardiomyocyte death involves necroptosis requires further investigation. Hence, we sought to test the hypothesis that RIP3‐depedent cardiomyocyte necroptosis contributes to ISO‐induced cardiac injury. Methods and Results Young adult mixed‐sex wild type (RIP3 +/+ ) or RIP3 global knockout (RIP3 −/− ) C57BL/6 mice were subject to two consecutive subcutaneous injections of ISO (85mg/kg body weight/injection, 24h interval) or vehicle, myocardial tissues were collected at 24h after the 2 nd ISO injection. Evan's blue dye (EBD) was administered (100ug/g body weight, i.p.) at 18h before tissues collection for the EBD‐based detection of increased cardiomyocyte membrane permeability, a hallmark of necrosis. In RIP3 +/+ mice, the ISO treatment significantly increased myocardial protein expression of RIP3 (both in the soluble and insoluble fractions), RIP1, RIP3 bund RIP1 (as detected by immunoprecipitation), and phosphorylated CaMKII and resulted in increased EDB uptake by a large number of cardiomyocytes ( p <0.01). By contrast, the elevation of RIP1 and the number of EBD‐positive cardiomyocytes, but not phosphorylated CaMKII, were significantly less in the RIP3 −/− mice subject to the same ISO treatment ( p <0.01). Conclusion Induction of myocardial injury by excessive β‐adrenergic receptor activation involves cardiomyocyte necroptosis via a RIP3‐dependent but CaMKII‐independent pathway. Support or Funding Information This work is supported in part by grants from the NIH [HL072166, HL085629, and HL131667] and the National Natural Science Foundation of China [81570278] This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .