Premium
PKC‐permitted elevation of sarcolemmal K ATP concentration may explain female‐specific resistance to myocardial infarction
Author(s) -
Edwards Andrew G.,
Rees Meredith L.,
Gioscia Rachel A.,
Zachman Derek K.,
Lynch Joshua M.,
Browder Jason C.,
Chicco Adam J.,
Moore Russell L.
Publication year - 2009
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2009.181040
Subject(s) - chelerythrine , protein kinase c , blockade , cardioprotection , medicine , endocrinology , ischemia , cardiology , kinase , chemistry , receptor , biochemistry
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 K ATP channel (sarcK ATP ), and protein kinase C (PKC). Here we investigate whether PKC‐mediated regulation of sarcK ATP 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 sarcK ATP 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 PKCɛ and sarcK ATP . 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 sarcK ATP 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 PKCɛ was reduced by Chel (p‐PKCɛ/PKCɛ: control, 0.43 ± 0.02; Chel, 0.29 ± 0.01; P < 0.01). We conclude that PKC‐mediated regulation of sarcK ATP may account for the physiologically sustainable dependence of SSC upon both PKC and sarcK ATP , and that this regulation involves PKC‐permitted enrichment of the female sarcolemma with sarcK ATP . As such, the PKC‐sarcK ATP axis may represent a target for sustainable prophylactic induction of cardioprotection.