TY - JOUR
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
N1 - Publisher Copyright:
© 2019 Elsevier B.V.
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.
KW - CaMKII
KW - Cardiac remodeling
KW - Crabp1
KW - Retinoic acid
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U2 - 10.1016/j.ejphar.2019.172485
DO - 10.1016/j.ejphar.2019.172485
M3 - Article
C2 - 31238067
AN - SCOPUS:85067868199
SN - 0014-2999
VL - 858
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
M1 - 172485
ER -