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Cardiac fibroblast GSK-3α aggravates ischemic cardiac injury by promoting fibrosis, inflammation, and impairing angiogenesis

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Abstract

Myocardial infarction (MI) is the leading cause of death worldwide. Glycogen synthase kinase-3 (GSK-3) has been considered to be a promising therapeutic target for cardiovascular diseases. GSK-3 is a family of ubiquitously expressed serine/threonine kinases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Previously, our group identified that cardiac fibroblast (FB) GSK-3β acts as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of FB-GSK-3α in MI pathology is not defined. To determine the role of FB-GSK-3α in MI-induced adverse cardiac remodeling, GSK-3α was deleted specifically in the residential fibroblast or myofibroblast (MyoFB) using tamoxifen (TAM) inducible Tcf21 or Periostin (Postn) promoter-driven Cre recombinase, respectively. Echocardiographic analysis revealed that FB- or MyoFB-specific GSK-3α deletion prevented the development of dilative remodeling and cardiac dysfunction. Morphometrics and histology studies confirmed improvement in capillary density and a remarkable reduction in hypertrophy and fibrosis in the KO group. We harvested the hearts at 4 weeks post-MI and analyzed signature genes of adverse remodeling. Specifically, qPCR analysis was performed to examine the gene panels of inflammation (TNFα, IL-6, IL-1β), fibrosis (COL1A1, COL3A1, COMP, Fibronectin-1, Latent TGF-β binding protein 2), and hypertrophy (ANP, BNP, MYH7). These molecular markers were essentially normalized due to FB-specific GSK-3α deletion. Further molecular studies confirmed that FB-GSK-3α could regulate NF-kB activation and expression of angiogenesis-related proteins. Our findings suggest that FB-GSK-3α plays a critical role in the pathological cardiac remodeling of ischemic hearts, therefore, it could be therapeutically targeted.

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Funding

This work was supported by research grants from the NHLBI (R01HL133290 and 1R01HL143074) to HL, American Heart Association (AHA CDA 933553) to ST.

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  1. Division of Cardiovascular Disease, UAB|The University of Alabama at Birmingham, 1720 2nd Ave South, Birmingham, AL, 35294-1913, USA

    Prachi Umbarkar, Suma Ejantkar, Sulivette Y. Ruiz Ramirez, Angelica Toro Cora, Qinkun Zhang, Sultan Tousif & Hind Lal

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Contributions

PU and HL conceived and designed the research; PU, SR, SE, and ST performed experiments; PU, SR, and SE analyzed data; PU, ST, and HL interpreted results of experiments; PU prepared figures; PU and HL drafted the manuscript; all authors contributed to editing, revision, and approved the final version of the manuscript.

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Correspondence to Prachi Umbarkar or Hind Lal.

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Umbarkar, P., Ejantkar, S., Ruiz Ramirez, S.Y. et al. Cardiac fibroblast GSK-3α aggravates ischemic cardiac injury by promoting fibrosis, inflammation, and impairing angiogenesis. Basic Res Cardiol 118, 35 (2023). https://doi.org/10.1007/s00395-023-01005-1

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