Global knockout of ROMK potassium channel worsens cardiac ischemia-reperfusion injury but cardiomyocyte-specific knockout does not: Implications for the identity of mitoKATP

Kyriakos N. Papanicolaou, Deepthi Ashok, Ting Liu, Tyler M. Bauer, Junhui Sun, Zhen Li, Eduardo da Costa, Charles Crepy D'Orleans, Sara Nathan, David J. Lefer, Elizabeth Murphy, Nazareno Paolocci, D. Brian Foster, Brian O'Rourke

Research output: Contribution to journalArticle

Abstract

The renal-outer-medullary‑potassium (ROMK) channel, mutated in Bartter's syndrome, regulates ion exchange in kidney, but its extra-renal functions remain unknown. Additionally, ROMK was postulated to be the pore-forming subunit of the mitochondrial ATP-sensitive K+ channel (mitoKATP), a mediator of cardioprotection. Using global and cardiomyocyte-specific knockout mice (ROMK-GKO and ROMK-CKO respectively), we characterize the effects of ROMK knockout on mitochondrial ion handling, the response to pharmacological KATP channel modulators, and ischemia/reperfusion (I/R) injury. Mitochondria from ROMK-GKO hearts exhibited a lower threshold for Ca2+-triggered permeability transition pore (mPTP) opening but normal matrix volume changes during oxidative phosphorylation. Isolated perfused ROMK-GKO hearts exhibited impaired functional recovery and increased infarct size when I/R was preceded by an ischemic preconditioning (IPC) protocol. Because ROMK-GKO mice exhibited severe renal defects and cardiac remodeling, we further characterized ROMK-CKO hearts to avoid confounding systemic effects. Mitochondria from ROMK-CKO hearts had unchanged matrix volume responses during oxidative phosphorylation and still swelled upon addition of a mitoKATP opener, but exhibited a lower threshold for mPTP opening, similar to GKO mitochondria. Nevertheless, I/R induced damage was not exacerbated in ROMK-CKO hearts, either ex vivo or in vivo. Lastly, we examined the response of ROMK-CKO hearts to ex vivo I/R injury with or without IPC and found that IPC still protected these hearts, suggesting that cardiomyocyte ROMK does not participate significantly in the cardioprotective pathway elicited by IPC. Collectively, our findings from these novel strains of mice suggest that cardiomyocyte ROMK is not a central mediator of mitoKATP function, although it can affect mPTP activation threshold.

Original languageEnglish (US)
Pages (from-to)176-189
Number of pages14
JournalJournal of Molecular and Cellular Cardiology
Volume139
DOIs
StatePublished - Feb 2020

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Keywords

  • Bartter's syndrome
  • Ischemic preconditioning
  • Kcnj1 or Kir1.1 or ROMK
  • Mitochondrial ATP-sensitive potassium channel
  • Mitochondrial permeability transition pore
  • Renal potassium channel

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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