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

Academic Article


  • 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, Il1β) 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.
  • Keywords

  • Bmal1, aging, circadian clock, diastolic dysfunction, extracellular matrix, inflammation, ARNTL Transcription Factors, Age Factors, Animals, Diastole, Disease Progression, Extracellular Matrix, Fibrosis, Gene Expression Regulation, Genotype, Hypertrophy, Left Ventricular, Inflammation, Inflammation Mediators, Male, Mice, Inbred C57BL, Mice, Knockout, Myocytes, Cardiac, Phenotype, RNA, Messenger, Signal Transduction, Smad2 Protein, Smad3 Protein, Time Factors, Transcription, Genetic, Transforming Growth Factor beta, Ventricular Dysfunction, Left, Ventricular Function, Left, Ventricular Remodeling
  • Digital Object Identifier (doi)

    Author List

  • Ingle KA; Kain V; Goel M; Prabhu SD; Young ME; Halade GV
  • Start Page

  • H1827
  • End Page

  • H1836
  • Volume

  • 309
  • Issue

  • 11