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

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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
Volume587
Issue number23
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Physiology

Cite this

Edwards, A. G., Rees, M. L., Gioscia, R. A., Zachman, D. K., Lynch, J. M., Browder, J. C., Chicco, A. J., & Moore, R. L. (2009). PKC-permitted elevation of sarcolemmal KATP concentration may explain female-specific resistance to myocardial infarction. Journal of Physiology, 587(23), 5723-5737. https://doi.org/10.1113/jphysiol.2009.181040