Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many important components of the cardiovascular system display circadian rhythmicity. In both humans and mice, cardiac damage from ischemia/reperfusion (I/R) is greatest at the transition from sleep to activity. The causes of this window of susceptibility are not fully understood. In the murine heart we have reported high amplitude circadian oscillations in the expression of the cardioprotective protein regulator of calcineurin 1 (Rcan1). This study was designed to test whether Rcan1 contributes to the circadian rhythm in cardiac protection from I/R damage. Wild type (WT), Rcan1 KO, and Rcan1-Tg mice, with cardiomyocyte-specific overexpression of Rcan1, were subjected to 45min of myocardial ischemia followed by 24h of reperfusion. Surgeries were performed either during the first 2h (AM) or during the last 2h (PM) of the animal's light phase. The area at risk was the same for all genotypes at either time point; however, in WT mice, PM-generated infarcts were 78% larger than AM-generated infarcts. Plasma cardiac troponin I levels were likewise greater in PM-operated animals. In Rcan1 KO mice there was no significant difference between the AM- and PM-operated hearts, which displayed greater indices of damage similar to that of PM-operated WT animals. Mice with cardiomyocyte-specific overexpression of human RCAN1, likewise, showed no time-of-day difference, but had smaller infarcts comparable to those of AM-operated WT mice. In vitro, cardiomyocytes depleted of RCAN1 were more sensitive to simulated I/R and the calcineurin inhibitor, FK506, restored protection. FK506 also conferred protection to PM-infarcted WT animals. Importantly, transcription of core circadian clock genes was not altered in Rcan1 KO hearts. These studies identify the calcineurin/Rcan1-signaling cascade as a potential therapeutic target through which to benefit from innate circadian changes in cardiac protection without disrupting core circadian oscillations that are essential to cardiovascular, metabolic, and mental health.
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PMID:Calcineurin and its regulator, RCAN1, confer time-of-day changes in susceptibility of the heart to ischemia/reperfusion. 2483 1

Mitochondrial dysfunction induced by myocardial ischemia is the primary cause of cardiac cell death. Specific removal of damaged mitochondria through mitophagy may be beneficial for cardiomyocyte protection against ischemia. Regulator of calcineurin 1-1L (Rcan1-1L) has been implicated in mitophagy induction in neurons. However, whether or not Rcan1-1L can evoke mitophagy in cardiomyocytes during hypoxia remains unknown. This study aims to investigate the effect of Rcan1-1L overexpression on cardiomyocytes during hypoxia and the possible underlying mechanism. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that Rcan1-1L overexpression inhibited cell growth under normoxic conditions, whereas Rcan1-1L overexpression significantly reversed the growth inhibition induced by hypoxia. The results of terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeling assay showed that cell apoptosis induced by hypoxia was markedly reduced by Rcan1-1L overexpression. In addition, Rcan1-1L overexpression inhibited the expression of the proapoptotic protein Bcl-2-associated death promoter and increased that of the antiapoptotic protein Bcl-2. Rcan1-1L overexpression opened the mitochondrial permeability transition pore and decreased mitochondrial mass. Meanwhile, the release of reactive oxygen species from mitochondria was suppressed by Rcan1-1L. Autophagy flow activation represented by mammalian target of rapamycin inhibition and microtubule-associated protein light chain 3 (LC3) upregulation was also demonstrated. Compared with endoplasmic reticulum and Golgi apparatus protein markers, the mitochondrial protein marker translocase of outer mitochondrial membranes 20 (TOM20) was downregulated by Rcan1-1L overexpression. Moreover, Rcan1-1L increased mitophagy receptor Parkin translocation into mitochondria from cytosol. Additionally, the effect of Rcan1-1L on cell growth, cell apoptosis and mitochondria mass was blocked by Parkin expression silencing. Overall, these data suggest that Rcan1-1L protects cardiomyocytes from hypoxia-induced apoptosis by inducing mitophagy partly through Parkin. This study provided novel insights into the prevention and treatment of ischemic heart disease.
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PMID:Regulator of calcineurin 1-1L protects cardiomyocytes against hypoxia-induced apoptosis via mitophagy. 2488 85

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Considerable efforts are needed to elucidate the underlying mechanisms for the prevention and treatment of CVDs. Regulator of calcineurin 1 (RCAN1) is involved in both development/maintenance of the cardiovascular system and the pathogenesis of CVDs. RCAN1 reduction protects against atherosclerosis by reducing the uptake of oxidized low-density lipoproteins, whereas RCAN1 has a protective effect on myocardial ischemia/reperfusion injury, myocardial hypertrophy and intramural hematoma/aortic rupture mainly mediated by maintaining mitochondrial function and inhibiting calcineurin and Rho kinase activity, respectively. In this review, the regulation and the function of RCAN1 are summarized. Moreover, the dysregulation of RCAN1 in CVDs is reviewed. In addition, the beneficial role of RCAN1 reduction in atherosclerosis and the protective role of RCAN1 in myocardial ischemia/reperfusion injury, myocardial hypertrophy and intramural hematoma /aortic rupture are discussed, as well as underlying mechanisms. Furthermore, the therapeutic potential and challenges of targeting RCAN1 for CVDs treatment are also discussed.
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PMID:RCAN1 in cardiovascular diseases: molecular mechanisms and a potential therapeutic target. 3326 91