Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2

Virag, Jitka A. I.; Dries, Jessica L.; Easton, Peter; Friesland, Amy; DeAntonio, Jon H; Chintalgattu, Vishnu; Cozzi, Emily; Lehmann, Brian D.; Ding, Jian; Lust, Robert M.

doi:10.1152/ajpheart.01280.2008

Cited by 51 publications

(48 citation statements)

References 49 publications

(56 reference statements)

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“…16 Per2 was selected for analysis, given that it is regulated by aldosterone in cardiomyocytes and that mice null for Per2 are protected from cardiac remodeling. 17 Per2 was upregulated at 8 days of DOC/salt in WT but not MyoMRKO mice, suggesting a potential role for cardiomyocyte MR signaling in the modulation of clock genes, although detailed time-course studies are required to fully characterize this response. Given that the cardiomyocyte circadian clock influences myocardial gene expression, heart rate, function, and tolerance to reperfusion injury, Per2 may represent a novel contributor to DOC/ salt-mediated cardiac pathology.…”

Section: Cardiomyocyte Mr and Collagen Depositionmentioning

confidence: 99%

Cardiomyocyte Mineralocorticoid Receptors Are Essential for Deoxycorticosterone/Salt-Mediated Inflammation and Cardiac Fibrosis

Rickard¹,

Morgan

Bienvenu

et al. 2012

Hypertension

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Because the role of mineralocorticoid receptors in specific cell types in cardiac remodeling remains unknown, we have compared cardiac responses with deoxycorticosterone/salt in cardiomyocyte mineralocorticoid receptor-null (MyoMRKO) and wild-type (WT) mice at 8 days and 8 weeks. No differences in cardiac function between untreated WT and MyoMRKO mice were found, whereas profibrotic markers were reduced in MyoMRKO hearts at baseline. At 8 days, MyoMRKO showed monocyte/macrophage recruitment equivalent to WT mice in response to deoxycorticosterone/salt but a suppression of markers of fibrosis compared with WT. At 8 weeks, MyoMRKO mice showed no deoxycorticosterone/salt-induced increase in inflammatory cell infiltration and collagen deposition or in proinflammatory gene expression. Although some profibrotic markers were equivalently increased in both genotypes, MyoMRKO mice also showed increased baseline levels of mRNA and protein for the transforming growth factor-β/connective tissue growth factor inhibitor decorin compared with WT that was accompanied by higher levels of matrix metalloproteinase 2/matrix metalloproteinase 9 activity. These data point to a direct role for cardiomyocyte mineralocorticoid receptor in both deoxycorticosterone/salt-induced tissue inflammation and remodeling and suggest potential mechanisms for the cardioprotective effects of selective mineralocorticoid receptor blockade in cardiomyocytes that may involve regulation of matrix metalloproteinase 2/matrix metalloproteinase 9 activity and the transforming growth factor-β-connective tissue growth factor profibrotic pathway.

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Section: Cardiomyocyte Mr and Collagen Depositionmentioning

confidence: 99%

Cardiomyocyte Mineralocorticoid Receptors Are Essential for Deoxycorticosterone/Salt-Mediated Inflammation and Cardiac Fibrosis

Rickard¹,

Morgan

Bienvenu

et al. 2012

Hypertension

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“…Analyses of gene expression profiles revealed that Ͼ10% of myocardial genes exhibit circadian rhythms (58). Recently, Virag et al (54) reported that functional deletion of the Per2 gene in knockout mice significantly reduced the size of MI. In the current study, we observed that expression of Per2 gene is downregulated, while Arntl gene expression is increased in transgenic Cd36-SHR compared with SHR controls, which suggests that the repressor activity of Per2 is reduced and thus its targets might be upregulated.…”

Section: Discussionmentioning

confidence: 99%

CD36 overexpression predisposes to arrhythmias but reduces infarct size in spontaneously hypertensive rats: gene expression profile analysis

Neckář

Šilhavý

Zidek

et al. 2012

Physiological Genomics

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Pravenec M. CD36 overexpression predisposes to arrhythmias but reduces infarct size in spontaneously hypertensive rats: gene expression profile analysis. Physiol Genomics 44: 173-182, 2012. First published November 29, 2011 doi:10.1152/physiolgenomics.00083.2011.-CD36 fatty acid translocase plays a key role in supplying heart with its major energy substrate, long-chain fatty acids (FA). Previously, we found that the spontaneously hypertensive rat (SHR) harbors a deletion variant of Cd36 gene that results in reduced transport of long-chain FA into cardiomyocytes and predisposes the SHR to cardiac hypertrophy. In the current study, we analyzed the effects of mutant Cd36 on susceptibility to ischemic ventricular arrhythmias and myocardial infarction in adult SHR-Cd36 transgenic rats with wild-type Cd36 compared with age-matched SHR controls. Using an open-chest model of coronary artery occlusion, we found that SHR-Cd36 transgenic rats showed profound arrhythmogenesis resulting in significantly increased duration of tachyarrhythmias (207 Ϯ 48 s vs. 55 Ϯ 21 s, P Ͻ 0.05), total number of premature ventricular complexes (2,623 Ϯ 517 vs. 849 Ϯ 250, P Ͻ 0.05) and arrhythmia score (3.86 Ϯ 0.18 vs. 3.13 Ϯ 0.13, P Ͻ 0.001). On the other hand, transgenic SHR compared with SHR controls showed significantly reduced infarct size (52.6 Ϯ 4.3% vs. 72.4 Ϯ 2.9% of area at risk, P Ͻ 0.001). Similar differences were observed in isolated perfused hearts, and the increased susceptibility of transgenic SHR to arrhythmias was abolished by reserpine, suggesting the involvement of catecholamines. To further search for possible molecular mechanisms of altered ischemic tolerance, we compared gene expression profiles in left ventricles dissected from 6-wk-old transgenic SHR vs. age-matched controls using Illumina-based sequencing. Circadian rhythms and oxidative phosphorylation were identified as the top KEGG pathways, while circadian rhythms, VDR/RXR activation, IGF1 signaling, and HMGB1 signaling were the top IPA canonical pathways potentially important for Cd36-mediated effects on ischemic tolerance. It can be concluded that transgenic expression of Cd36 plays an important role in modulating the incidence and severity of ischemic and reperfusion ventricular arrhythmias and myocardial infarct size induced by coronary artery occlusion. The proarrhythmic effect of Cd36 transgene appears to be dependent on adrenergic stimulation. myocardial infarction CARDIOVASCULAR DISEASES, SPECIFICALLY coronary heart disease and myocardial infarction (MI), are the leading cause of morbidity and mortality in developed countries. Most cardiac phenotypes including cardiac mass, arrhythmias, infarct size, and susceptibility to heart failure are quantitative traits determined by genetic and environmental factors such as diet or stress. Additional "extracardiac" factors that cause a predisposition to coronary heart disease include proatherogenic factors such as high blood pressure, abnormal lipid profiles, or insulin resistance. Despite advances in the treatment...

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“…13 Studies by Virag et al showed that mPer2 mutant (functional null) mice have reduced infarct by 43% after nonreperfused MI, by 69% after ischemia/ reperfusion, and by 75% after preconditioned ischemia/ reperfusion, respectively. 15,16 However, Eckle et al found that mPer2 mutant mice had larger infarct sizes and loss of the cardioprotection conferred by ischemic preconditioning when compared with wild-type mice. 100 The same group also found a reduction in infarct size at ZT12 and ZT18 compared with ZT0, which is different from the first report by Durgan et al 13 Although different surgical techniques and protocols (time-of-day) were used and may have contributed to the different results, more studies are needed to elucidate the reasons for this discrepancy.…”

Section: Ischemia/reperfusionmentioning

confidence: 99%

“…[5][6][7][8] In addition, disruption of the circadian rhythm either in the brain (central clock) or in the peripheral tissues (peripheral clock) leads to cardiovascular disease in both human and animal models. [9][10][11][12][13][14][15][16][17][18][19] In this review, we summarize our current understanding of the interplay between circadian regulation and cardiovascular disease, as well as future directions in development of therapy.…”

Section: Introductionmentioning

confidence: 99%

Circadian rhythm and cardiovascular disorders

Zhang¹,

Sabeh²,

Jain³

2014

CPT

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Abstract:Circadian rhythmicity affects all living organisms on earth. Central and peripheral cellular clocks have the ability to oscillate and be entrained to environmental cues, thus allowing organisms to anticipate and synchronize their physiologic processes and behavior to recurring daily environmental alterations. Disruption of the circadian rhythm in modern life, such as by shift work and jet travel, leads to dyssynchrony of the central and peripheral clocks, and is an independent risk factor for cardiovascular disease and the metabolic syndrome. Aging has also been associated with attenuated cellular rhythmicity. Here we summarize the clinical observations linking cardiovascular health to circadian rhythm. In addition, we discuss recent advances in experimental models for understanding the clock machinery in terms of a variety of physiologic processes within the cardiovascular system. Together, these studies build the foundation for applying our knowledge of circadian biology to the development of novel therapy for cardiovascular disorders.

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Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2

Abstract: Virag JA, Dries JL, Easton PR, Friesland AM, DeAntonio JH, Chintalgattu V, Cozzi E, Lehmann BD, Ding JM, Lust RM. Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2.

Cited by 51 publications

References 49 publications

Cardiomyocyte Mineralocorticoid Receptors Are Essential for Deoxycorticosterone/Salt-Mediated Inflammation and Cardiac Fibrosis

Cardiomyocyte Mineralocorticoid Receptors Are Essential for Deoxycorticosterone/Salt-Mediated Inflammation and Cardiac Fibrosis

CD36 overexpression predisposes to arrhythmias but reduces infarct size in spontaneously hypertensive rats: gene expression profile analysis

Circadian rhythm and cardiovascular disorders

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