PKC-permitted elevation of sarcolemmal KATP concentration may explain female-specific resistance to myocardial infarction

Andrew G. Edwards, Meredith L. Rees, Rachel A. Gioscia, Derek K. Zachman, Joshua M. Lynch, Jason C. Browder, Adam J. Chicco, Russell L. Moore

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16 Scopus citations


The female myocardium, relative to that of the male, exhibits sustained resistance to ischaemic tissue injury, a phenomenon termed sex-specific cardioprotection (SSC). SSC is dependent upon the sarcolemmal KATP channel (sarcKATP), and protein kinase C (PKC). Here we investigate whether PKC-mediated regulation of sarcKATP concentration can explain this endogenous form of protection. Hearts from male (M) and female (F) rats were Langendorff-perfused for 30 min prior to either regional ischaemia-reperfusion (I/R), or global ischaemia (GISC). For both protocols, pre-ischaemic blockade of PKC was achieved by chelerythrine (Chel) in male (M + C) and female (F + C) hearts. Additional female hearts underwent sarcKATP antagonism during I/R by HMR-1098 (HMR), either alone or in combination with Chel (HMR + Chel). GISC hearts were fractionated to assess cellular distribution of PKCe{open} and sarcKATP. Sex-specific infarct resistance was apparent under control I/R (F, 23 ± 3% vs. M, 36 ± 4%, P < 0.05) and abolished by Chel (F + C, 36 ± 3%). Female infarct resistance was susceptible to sarcKATP blockade (Control, 16 ± 2% vs. HMR, 27 ± 3%), and PKC blockade had no additional effect (HMR + Chel, 26 ± 2%). The prevalence of Kir6.2 and SUR2 was higher in the sarcolemmal fractions of females (Kir6.2: F, 1.24 ± 0.07 vs. M, 1.02 ± 0.06; SUR2: F, 3.16 ± 0.22 vs. M, 2.45 ± 0.09; ratio units), but normalized by Chel (Kir6.2: F, 1.06 ± 0.07 vs. M, 0.99 ± 0.06; SUR2: F, 2.99 ± 0.09 vs. M, 2.82 ± 0.22, M; ratio units). Phosphorylation of sarcolemmal PKCe{open} was reduced by Chel (p-PKCe{open}/PKCe{open}: control, 0.43 ± 0.02; Chel, 0.29 ± 0.01; P < 0.01). We conclude that PKC-mediated regulation of sarcKATP may account for the physiologically sustainable dependence of SSC upon both PKC and sarcKATP, and that this regulation involves PKC-permitted enrichment of the female sarcolemma with sarcKATP. As such, the PKC-sarcKATP axis may represent a target for sustainable prophylactic induction of cardioprotection.

Original languageEnglish (US)
Pages (from-to)5723-5737
Number of pages15
JournalJournal of Physiology
Issue number23
StatePublished - Dec 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Physiology


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