Response by Prisco and Prins to Letter Regarding Article, "Inflammatory Glycoprotein 130 Signaling Links Changes in Microtubules and Junctophilin-2 to Altered Mitochondrial Metabolism and Right Ventricular Contractility".

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HomeCirculation: Heart FailureVol. 15, No. 8Response by Prisco and Prins to Letter Regarding Article, “Inflammatory Glycoprotein 130 Signaling Links Changes in Microtubules and Junctophilin-2 to Altered Mitochondrial Metabolism and Right Ventricular Contractility” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse by Prisco and Prins to Letter Regarding Article, “Inflammatory Glycoprotein 130 Signaling Links Changes in Microtubules and Junctophilin-2 to Altered Mitochondrial Metabolism and Right Ventricular Contractility” Sasha Z. Prisco, MD, PhD and Kurt W. Prins, MD, PhD Sasha Z. PriscoSasha Z. Prisco https://orcid.org/0000-0002-9059-0635 Cardiovascular Division, Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis. Search for more papers by this author and Kurt W. PrinsKurt W. Prins https://orcid.org/0000-0002-0364-6742 Cardiovascular Division, Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis. Search for more papers by this author Originally published27 Jun 2022https://doi.org/10.1161/CIRCHEARTFAILURE.122.009570Circulation: Heart Failure. 2022;15Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 27, 2022: Ahead of Print In Response:We thank Li et al for raising important questions about our recent article.1 These authors highlight limitations to our work including nonspecificity of the small molecule antagonist as compared with a genetic knockout, which we do not dispute. However, a small molecule inhibitor usually does not recapitulate a genetic knockout phenotype. Generally, an antagonist only partially blocks signaling and does not completely suppress it. Consistent with this, our article shows phosphorylated STAT3 (signal transducer and activator of transcription 3) levels in the right ventricle of SC-144 treated animals are still slightly higher than control.1In addition, we would like to highlight multiple papers from several independent laboratories demonstrating excess GP130 (glycoprotein 130)–STAT3 signaling results in cardiac dysfunction. First, cardiac-specific overexpression of constitutively active GP130 is even more detrimental than GP130 knockout in a myocardial infarction model.2 Importantly, the reduction of STAT3 protein levels mitigates this phenotype.2 Second, knockout of SOCS3 (suppressor of cytokine signaling-3) leads to upregulation of the GP130–STAT3 axis and depresses cardiac function.3 However, cardiac-specific deletion of GP130 abrogates STAT3 activation and significantly extends survival in SOCS3 knockout mice.3 Third, expression of a dominant-negative GP130 transgene prevents the increase in STAT3 phosphorylation and cardiac hypertrophy along with normalizing sarcoplasmic reticulum Ca2+ ATPase 2 and brain natriuretic peptides mRNA levels in an abdominal aortic banding model.4 Fourth, use of a GP130 neutralizing antibody preserves left ventricular ejection fraction in a rodent of myocardial infarction.5 Our data appear to be congruent with multiple other groups demonstrating a pathological effect of excess GP130–STAT3 activation in cardiac biology. Thus, our synthesis of the available literature is that both the absence of and excess GP130 signaling have detrimental effects on cardiac function.We focused on the JAK (Janus kinase)/STAT3 signaling pathway because STAT3 is believed to the predominant intracellular effector protein for GP130, and STAT3 is involved in microtubule remodeling. In the original description of SC-144, STAT3 and AKT activation with 2 GP130 cytokines was inhibited, but AKT–STAT3 signaling induced by GP130-independent molecules was not. Future studies evaluating the effects of SC-144 on other GP130 signaling pathways (ERK–MAPK [extracellular signal-regulated kinase–mitogen-activated protein kinase], PI3K/AKT [phosphoinositide 3-kinases/protein kinase B], and Src-YAP [Yes-associated protein]) in the right ventricle along with determining the therapeutic effects in a STAT3 antagonized model are warranted.Finally, because we used differentiated H9c2 cells, which have extremely low proliferation rates, we propose depressed mitochondrial function is not solely due to changes in mitosis. However, we agree additional work needs to be performed to understand the microtubule-mitochondrial link in cardiac biology.Article InformationSources of FundingDr Prisco is funded by National Institutes of Health (NIH) F32 HL154533 and a University of Minnesota Clinical and Translational Science award (NIH UL1 TR002494). Dr Prins is funded by NIH K08 HL140100 and R01s HL162927 and HL158795 and American Lung Association Innovative Award IA-816386. The content is solely the responsibility of the authors and does not represent the official views of the NIH or any other funding sources.Disclosures Drs Prisco and Prins have a provisional patent for use of SC-144 in right ventricular dysfunction. Dr Prins served on an advisory board for Actelion and Edwards and receives grant funding from United Therapeutics.FootnotesFor Sources of Funding and Disclosures, see pages 824 and 825.