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CRABP1 protects the heart from isoproterenol-induced acute and chronic remodeling.

Published on Mar 1, 2018in Journal of Endocrinology4.381
· DOI :10.1530/JOE-17-0613
Sung Wook Park15
Estimated H-index: 15
,
Shawna D. Persaud8
Estimated H-index: 8
(UMN: University of Minnesota)
+ 3 AuthorsLi-Na Wei39
Estimated H-index: 39
Abstract
: Excessive and/or persistent activation of calcium-calmodulin protein kinase II (CaMKII) is detrimental in acute and chronic cardiac injury. However, intrinsic regulators of CaMKII activity are poorly understood. We find that cellular retinoic acid-binding protein 1 (CRABP1) directly interacts with CaMKII and uncover a functional role for CRABP1 in regulating CaMKII activation. We generated Crabp1-null mice (CKO) in C57BL/6J background for pathophysiological studies. CKO mice develop hypertrophy as adults, exhibiting significant left ventricular dilation with reduced ejection fraction at the baseline cardiac function. Interestingly, CKO mice have elevated basal CaMKII phosphorylation at T287, and phosphorylation on its substrate phospholamban (PLN) at T17. Acute isoproterenol (ISO) challenge (80 mg/kg two doses in 1 day) causes more severe apoptosis and necrosis in CKO hearts, and treatment with a CaMKII inhibitor KN-93 protects CKO mice from this injury. Chronic (30 mg/kg/day) ISO challenge also significantly increases hypertrophy and fibrosis in CKO mice as compared to WT. In wild-type mice, CRABP1 expression is increased in early stages of ISO challenge and eventually reduces to the basal level. Mechanistically, CRABP1 directly inhibits CaMKII by competing with calmodulin (CaM) for CaMKII interaction. This study demonstrates increased susceptibility of CKO mice to ISO-induced acute and chronic cardiac injury due to, at least in part, elevated CaMKII activity. Deleting Crabp1 results in reduced baseline cardiac function and aggravated damage challenged with acute and persistent β-adrenergic stimulation. This is the first report of a physiological role of CRABP1 as an endogenous regulator of CaMKII, which protects the heart from ISO-induced damage.
  • References (43)
  • Citations (6)
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References43
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#2Mark E. Anderson (Johns Hopkins University)H-Index: 63
Abstract Sustained Ca 2 + /calmodulin-dependent kinase II (CaMKII) activation plays a central role in the pathogenesis of a variety of cardiac diseases. Emerging evidence suggests CaMKII evoked programmed cell death, including apoptosis and necroptosis, is one of the key underlying mechanisms for the detrimental effect of sustained CaMKII activation. CaMKII integrates β-adrenergic, Gq coupled receptor, reactive oxygen species (ROS), hyperglycemia, and pro-death cytokine signaling to elicit myoca...
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#1Michael M. Kreusser (Heidelberg University)H-Index: 15
#2Lorenz H. Lehmann (Heidelberg University)H-Index: 15
Last. Johannes Backs (Heidelberg University)H-Index: 36
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CaM kinase II (CaMKII) has been suggested to drive pathological cardiac remodeling and heart failure. However, the evidence provided so far is based on inhibitory strategies using chemical compounds and peptides that also exert off-target effects and followed exclusively preventive strategies. Therefore, the aim of this study was to investigate whether specific CaMKII inhibition after the onset of cardiac stress delays or reverses maladaptive cardiac remodeling and dysfunction. Combined genetic ...
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#1Shangcheng Xu (Third Military Medical University)H-Index: 3
#2Pei Wang (UW: University of Washington)H-Index: 5
Last. Wang Wang (UW: University of Washington)H-Index: 19
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Mitochondrial permeability transition pore (mPTP) is involved in cardiac dysfunction during chronic β-adrenergic receptor (β-AR) stimulation. The mechanism by which chronic β-AR stimulation leads to mPTP openings is elusive. Here, we show that chronic administration of isoproterenol (ISO) persistently increases the frequency of mPTP openings followed by mitochondrial damage and cardiac dysfunction. Mechanistically, this effect is mediated by phosphorylation of mitochondrial fission protein, dyna...
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