title: Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2.
abstract: Variations in circadian rhythms are evident in the incidence of cardiovascular disease, and the risk of cardiovascular events increases when rhythms are disrupted. The suprachiasmatic nucleus is the central circadian pacemaker that regulates the daily rhythm of peripheral organs. Diurnal rhythms have more recently been shown to exist in myocardial tissue and are involved in metabolism and contractile function. Thus we sought to determine whether the functional deletion of the circadian rhythm mouse periodic gene 2 (mPer2) would protect the heart against ischemic injury. Nonreperfused myocardial infarction was induced in anesthetized, ventilated C57 (n = 17) and mPer2 mutant (mPer2-M; n = 15) mice via permanent ligation of the left anterior descending coronary artery. At 4 days post-myocardial infarction, we observed a 43% reduction of infarct area in mPer2-M mice compared with wild-type mice. This is coincident with 25% less macrophage infiltration, 43% higher capillary density, 17% increase in hypertrophy, and 15% less cardiomyocyte apoptosis in the infarct zone. Also, matrix metalloproteinase-9 was expressed in inflammatory cells in both groups, but total protein was 40% higher in wild-type mice, whereas it was not elevated in mPer2-M mice in response to injury. The functional deletion of the mPer2 gene reduces the severity of myocardial infarct injury by limiting the inflammatory response, reducing apoptosis, and inducing cardiomyocyte hypertrophy, thus preserving cardiac function. These findings collectively imply that the disruption of the circadian clock gene mPer2 is protective. Understanding the interactions between circadian rhythm genes and cardiovascular disease may provide insights into potential preventative and therapeutic strategies for susceptible populations.
authors.affiliation: Dept. of Physiology, East Carolina Univ., Greenville, NC 27834, USA. viragj@ecu.edu
authors.forename: Jitka A I
authors.initials: JA
authors.lastname: Virag
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Dries
authors.forename: Peter R
authors.initials: PR
authors.lastname: Easton
authors.forename: Amy M
authors.initials: AM
authors.lastname: Friesland
authors.forename: Jon H
authors.initials: JH
authors.lastname: DeAntonio
authors.forename: Vishnu
authors.initials: V
authors.lastname: Chintalgattu
authors.forename: Emily
authors.initials: E
authors.lastname: Cozzi
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lehmann
authors.forename: Jian M
authors.initials: JM
authors.lastname: Ding
authors.forename: Robert M
authors.initials: RM
authors.lastname: Lust
mesh_terms: D000818:Animals; D017209:Apoptosis; D003331:Coronary Vessels / Q000503:physiopathology; D004195:Disease Models, Animal; D017353:Gene Deletion; D006984:Hypertrophy; D008026:Ligation / Q000009:adverse effects; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009203:Myocardial Infarction / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D056950:Period Circadian Proteins / Q000235:genetics*
chemical_list: C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D020780:Matrix Metalloproteinase 9