title: PKC-permitted elevation of sarcolemmal KATP concentration may explain female-specific resistance to myocardial infarction.
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 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 PKC 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 PKC was reduced by Chel (p-PKC/PKC: 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.
authors.affiliation: University of Colorado at Boulder, 354 UCB, Boulder, CO 80309-0354, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Edwards
authors.forename: Meredith L
authors.initials: ML
authors.lastname: Rees
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gioscia
authors.forename: Derek K
authors.initials: DK
authors.lastname: Zachman
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Lynch
authors.forename: Jason C
authors.initials: JC
authors.lastname: Browder
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Chicco
authors.forename: Russell L
authors.initials: RL
authors.lastname: Moore
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism / Q000502:physiology; D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D015153:Blotting, Western; D003326:Coronary Circulation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000378:metabolism / Q000502:physiology; D012508:Sarcolemma / Q000378:metabolism*; D012727:Sex Characteristics; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013347:Subcellular Fractions / Q000502:physiology; D064233:Sulfonylurea Receptors; D016277:Ventricular Function, Left / Q000502:physiology; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D011955:Receptors, Drug; D019831:Sodium-Calcium Exchanger; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577512:Abcc9 protein, rat; C110374:sodium-calcium exchanger 1; C016299:chelerythrine