All-trans retinoic acid attenuates isoproterenol-induced cardiac dysfunction through Crabp1 to dampen CaMKII activation

Sung Wook Park, Jennifer Nhieu, Yi Wei Lin, Li Na Wei

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Inhibiting Ca2+/calmodulin-dependent protein kinase II (CaMKII) over activation can decrease detrimental cardiac remodeling that leads to dilated cardiomyopathy, cell death, and heart failure. We previously showed that cellular retinoic acid binding protein 1 (Crabp1) knockout mice (CKO) exhibited a more severe isoproterenol (ISO)-induced heart failure and cardiac remodeling phenotype with elevated CaMKII activity in the heart, suggesting a cardiac-protective function of Crabp1 through modulating CaMKII activity. Here we examine whether the highly selective, endogenous ligand of Crabp1, all-trans retinoic acid (RA), can attenuate ISO-induced cardiac dysfunction. We also examine if this attenuation involves Crabp1 and the inhibition of CaMKII. RA pre-treatment followed by ISO challenge effectively restores ejection fraction in wild type, but not in CKO mice. This is correlated with reduced CaMKII auto-phosphorylation at T287 and phospholamban phosphorylation at T17, a substrate of CaMKII. RA pretreatment also reduces ISO-induced apoptosis in WT heart. Cell culture experiments confirm that RA inhibits CaMKII phosphorylation, which requires Crabp1. Molecular data reveal interaction of Crabp1 with the kinase and regulatory domains of CaMKII, and that RA selectively enhances Crabp1 interaction with the regulatory domain, suggesting a potential regulatory role for holo-Crabp1 in CaMKII activation. Together, these data demonstrate that RA bound Crabp1 plays a protective role in β-adrenergic stimulated cardiac remodeling, which is partially attributed to its dampening CaMKII activation. Targeting Crabp1 provides a potentially new therapeutic strategy for managing heart diseases.

Original languageEnglish (US)
Article number172485
JournalEuropean Journal of Pharmacology
Volume858
DOIs
StatePublished - Sep 5 2019

Bibliographical note

Funding Information:
This study was supported by NIH grants DK54733 , DK60521 , and the Dean's Commitment and the Distinguished McKnight Professorship of University of Minnesota to LNW.

Keywords

  • CaMKII
  • Cardiac remodeling
  • Crabp1
  • Retinoic acid

PubMed: MeSH publication types

  • Journal Article

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