期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 139, 期 -, 页码 176-189出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2020.01.010
关键词
Kcnj1 or Kir1.1 or ROMK; Mitochondrial ATP-sensitive potassium channel; Ischemic preconditioning; Mitochondrial permeability transition pore; Renal potassium channel; Bartter's syndrome
资金
- AHA Postdoctoral fellowship [15POST24700006]
- AHA Scientist Development Grant [12SDG12060056]
- NIH [K12 HL141952]
- NIH F31 grant [HL134198]
- AHA Transformational Project Award [18TPA34170575]
- [ZIA-HL002066]
- [R01HL137259]
- [RO1HL134821]
- [RO1HL136918]
- [R01HL134821]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL002066] Funding Source: NIH RePORTER
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 poreforming subunit of the mitochondrial ATP-sensitive 10 - channel (mitoK(ATP)), 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 mitochondria] 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 mitoK(ATP) 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 mitoK(ATP) function, although it can affect mPTP activation threshold.
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