843.1 - NOS isoforms facilitate Ca2+ -cycling-dependent and -independent cardiac contractility
Tuesday, April 5, 2022
10:45 AM – 10:48 AM
Room: ASPET Poster Discussion Area, Exhibit Hall Booth #1418 - Pennsylvania Convention Center
Introduction: Experience the daily ASPET datablitz, a rapid-fire oral presentation of research. Ten poster presenters each day will present three minute short talks in the ASPET poster discussion lounge in the poster hall (Aisle 1400). These brief snippets of research are an introduction to their full presentations that will take place at their poster boards afterwards. You won’t want to miss this fast-paced overview of the most exciting science of the day.
Ying Wang (University of California), MeiMi Zhao (University of California), Gabriela Rivera (University of California), Bing Xu (University of California), Vaseem Mir (University of California), Raghu Reddy (University of California), Yang Xiang (University of California)
Increasing biased G-protein coupled receptor (GPCR) drugs are now under clinical investigation. More understanding of the biased β-adrenergic receptor (β-AR) signaling is urgently required for a better cardiovascular drug. Here we found that two nitric oxide synthase (NOS) isotypes, NOS1, and NOS3 coupled with β1ARs and transduce distinct β1AR-cGMP signaling at sarcoplasmic reticulum and myofilament microdomain, respectively. Intriguingly, activation of NOS1 enhanced contractility and Ca2+ cycling, whereas NOS3 promoted contraction without affecting intracellular Ca2+. Quantitative proteomic revealed that NOS3 activation increased phosphorylation of myosin proteins including myosin binding protein C (MyBP-C), myosin light chain kinase (MYLK) and myosin phosphatase target subunit 1 (MYPT1), to enhance contractility by Ca2+sensitization. Moreover, in heart failure, excessive adrenergic stimulation dissociated β1AR from NOS1 and impaired the NOS1-cGMP signaling. Accordingly, stimulating NOS3 but NOS1 enhances systolic cardiac contraction in failing mice without rousing intracellular Ca2+. We propose NOS facilitate biased β1AR-cGMP signaling via Ca2+-dependent or independent mechanisms and define NOS3-cGMP as specific therapeutic strategy targeting myofilament for heart failure.
Support or Funding Information
American Heart Association (AHA) Postdoctoral Fellowship (YW 830512)
