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Publication : Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation.

First Author  Ingle KA Year  2015
Journal  Am J Physiol Heart Circ Physiol Volume  309
Issue  11 Pages  H1827-36
PubMed ID  26432841 Mgi Jnum  J:230671
Mgi Id  MGI:5763524 Doi  10.1152/ajpheart.00608.2015
Citation  Ingle KA, et al. (2015) Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation. Am J Physiol Heart Circ Physiol 309(11):H1827-36
abstractText  The mammalian circadian clock consists of multiple transcriptional regulators that coordinate biological processes in a time-of-day-dependent manner. Cardiomyocyte-specific deletion of the circadian clock component, Bmal1 (aryl hydrocarbon receptor nuclear translocator-like protein 1), leads to age-dependent dilated cardiomyopathy and decreased lifespan in mice. We investigated whether cardiomyocyte-specific Bmal1 knockout (CBK) mice display early alterations in cardiac diastolic function, extracellular matrix (ECM) remodeling, and inflammation modulators by investigating CBK mice and littermate controls at 8 and 28 wk of age (i.e., prior to overt systolic dysfunction). Left ventricles of CBK mice exhibited (P < 0.05): 1) progressive abnormal diastolic septal annular wall motion and reduced pulmonary venous flow only at 28 wk of age; 2) progressive worsening of fibrosis in the interstitial and endocardial regions from 8 to 28 wk of age; 3) increased (>1.5 fold) expression of collagen I and III, as well as the matrix metalloproteinases MMP-9, MMP-13, and MMP-14 at 28 wk of age; 4) increased transcript levels of neutrophil chemotaxis and leukocyte migration genes (Ccl2, Ccl8, Cxcl2, Cxcl1, Cxcr2, Il1beta) with no change in Il-10 and Il-13 genes expression; and 5) decreased levels of 5-LOX, HO-1 and COX-2, enzymes indicating impaired resolution of inflammation. In conclusion, genetic disruption of the cardiomyocyte circadian clock results in diastolic dysfunction, adverse ECM remodeling, and proinflammatory gene expression profiles in the mouse heart, indicating signs of early cardiac aging in CBK mice.
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