This month on Episode 43 of Discover CircRes, guest host Nicole Purcell highlights two original research articles featured in the December 2 issue of Circulation Research. This episode also features an interview with Drs Aaron Phillips and Kevin O'Gallagher about their study, The Effect of a Neuronal Nitric Oxide Synthase Inhibitor on Neurovascular Regulation in Humans.   Article highlights:   Akerberg, et al. RBPMS2 Regulates RNA Splicing in Cardiomyocytes   Lv, et al. Cardiac Protection by MG53-S255A Mutant   Nicole Purcell:             Hi and welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I am your host, Dr Nicole Purcell, from the Huntington Medical Research Institutes in Pasadena, California, and today I will be highlighting two articles from our December 2 issue of Circulation Research. I'll also have a chat with Drs Aaron Phillips and Kevin O'Gallagher about their study, The Effect of a Neuronal Nitric Oxide Synthase Inhibitor on Neurovascular Regulation in Humans.   Nicole Purcell:             But before I get to the interview, here are a few article highlights. The first article we're going to highlight is RBPMS2 Is a Myocardial Enriched Splicing Regulator Required for Cardiac Function. This comes from Boston Children's Hospital with first author Dr Alexander Akerberg, and corresponding author Dr Jeffrey Burns. RNA splicing, along with transcription control and post-translational modifications, is a mechanism for fine tuning the expression of a gene for a particular purpose in a particular tissue. Factors that control splicing are thus often enriched in certain cell types. The factor, RBPMS2, for example, is enriched in the myocytes of amphibians, fish, birds and mammals.  This conserve tissue specificity suggesting essential role of RBPMS2 in heart function.   Akerberg and colleagues now confirm this is indeed the case. They generated zebra fish embryos and human cardiomyocytes lacking RBPMS2, and found the fish suffered early cardiac dysfunction by 48 hours post fertilization. The animal's hearts had reduced ejection fractions, compared with the hearts of controlled fish. At the cellular level, the RBPMS2 lacking fish cardiomyocytes displayed malformed sarcomere fibers and disrupted calcium handling, both of which were also seen in the RBPMS2 deficient human cardiomyocytes. Furthermore, RNA sequencing experiments revealed a conserve set of 29 genes in the RBPMS2-lacking fish and human cells that were incorrectly spliced. In revealing the essential cardiac role of RBPMS2 and its RNA targets, the work provides new molecular details for understanding vertebrate heart function and disease, say the team.   Nicole Purcell:             Our second article being highlighted is Blocking MG53 Serine 255 Phosphorylation Protects Diabetic Heart from Ischemic Injury. This comes from Peking University with first authors, Fengxiang L, Yingfan Wang and Dan Shan, as well as corresponding author Dr Rui-Ping Xiao. Midsegment 53, or MG53, is a recently discovered muscle-specific protein that is an essential component of the cell membrane repair machinery with cardioprotective effects. MG53 thus has therapeutic potential, but for patients whose heart disease is linked to type 2 diabetes, there's a problem. MG53 also tags certain cellular proteins for destruction, including the insulin receptor and the insulin signaling factor, IRS1. Loss of these factors could worsen insulin resistance. lev and colleagues therefore investigate whether MG53 could be tweaked to provide protection without the diabetes downside.   Nicole Purcell:             They discovered the phosphorylation of MG53 at serine 255 is required for its role in protein destruction, and that a mutant version of MG53, incapable of this phosphorylation, MG53 serine to 255 alanine mutant, could still promote cardiomyocyte survival, and protect the ce