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

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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

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Retinoic Acid Receptors
Tretinoin
Isoproterenol
Phosphorylation
Knockout Mice
Heart Failure
Dilated Cardiomyopathy
Adrenergic Agents
Heart Diseases
Cell Death
Phosphotransferases
Cell Culture Techniques
Apoptosis
Ligands
Phenotype

Keywords

  • CaMKII
  • Cardiac remodeling
  • Crabp1
  • Retinoic acid

PubMed: MeSH publication types

  • Journal Article

Cite this

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title = "All-trans retinoic acid attenuates isoproterenol-induced cardiac dysfunction through Crabp1 to dampen CaMKII activation",
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.",
keywords = "CaMKII, Cardiac remodeling, Crabp1, Retinoic acid",
author = "Park, {Sung Wook} and Jennifer Nhieu and Yi-Wei Lin and Li-Na Wei",
year = "2019",
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T1 - All-trans retinoic acid attenuates isoproterenol-induced cardiac dysfunction through Crabp1 to dampen CaMKII activation

AU - Park, Sung Wook

AU - Nhieu, Jennifer

AU - Lin, Yi-Wei

AU - Wei, Li-Na

PY - 2019/9/5

Y1 - 2019/9/5

N2 - 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.

AB - 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.

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