No 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 PKCε 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%). 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.

Protein modifications modulate nearly every aspect of cell biology in organisms, ranging from Archaea to Eukaryotes. The earliest evidence of covalent protein modifications was found in the early 20th century by studying the amino acid composition of proteins by chemical hydrolysis. These discoveries challenged what defined a canonical amino acid. The advent and rapid adoption of mass-spectrometry-based proteomics in the latter part of the 20th century enabled a veritable explosion in the number of known protein modifications, with more than 500 discrete modifications counted today. Now, new computational tools in data science, machine learning, and artificial intelligence are poised to allow researchers to make significant progress in discovering new protein modifications and determining their function. In this review, we take an opportunity to revisit the historical discovery of key post-translational modifications, quantify the current landscape of covalent protein adducts, and assess the role that new computational tools will play in the future of this field.