کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8474997 | 1550441 | 2013 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Cyclic nucleotide phosphodiesterase 3A1 protects the heart against ischemia-reperfusion injury
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کلمات کلیدی
TNCMILLVPICERLVDdLVDsPLBSerca2β-ARPDE3AGAPDHAARpKaBcl-2I/R - I / RTnI - TNIMyocardial injury - آسیب میوکاردMyocardial infarction - آنفارکتوس میوکاردCSA - ایالات مؤتلفهٔ آمریکاISO - ایزوisoproterenol - ایزوپروترنولischemia/reperfusion - ایسکمی / رپرفیوژنleft ventricle - بطن چپTroponin C - تروپونین CTroponin I - تروپونین ITUNEL - تونلROL - رولRolipram - رولیرامامInducible cAMP early repressor - سرکوب کننده اولیه cAMP قابل انعطاف استtibia length - طول تیبیاphospholamban - فسفولامبنleft ventricular systolic pressure - فشار سیستولیک بطن چپleft ventricular diastolic diameter - قطر دیاستولیک بطن چپLAD - لادوB-cell lymphoma 2 - لنفوم سلول B 2cross-sectional area - مقطع عرضیarea at risk - منطقه در معرض خطر استTransgenic mice - موش ترانس ژنیکwild-type mice - موش های وحشیMilrinone - میلرینوlung weight - وزن ریهHeart weight - وزن قلبleft anterior descending - چپ قدامی نزولیejection fraction - کسری خروجیglyceraldehyde-3-phosphate dehydrogenase - گلیسرالیدید-3-فسفات دهیدروژنازbeta-adrenergic receptor - گیرنده بتا آدرنرژیک
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیولوژی سلول
پیش نمایش صفحه اول مقاله
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چکیده انگلیسی
Phosphodiesterase 3A (PDE3A) is a major regulator of cAMP in cardiomyocytes. PDE3 inhibitors are used for acute treatment of congestive heart failure, but are associated with increased incidence of arrhythmias and sudden death with long-term use. We previously reported that chronic PDE3A downregulation or inhibition induced myocyte apoptosis in vitro. However, the cardiac protective effect of PDE3A has not been demonstrated in vivo in disease models. In this study, we examined the role of PDE3A in regulating myocardial function and survival in vivo using genetically engineered transgenic mice with myocardial overexpression of the PDE3A1 isozyme (TG). TG mice have reduced cardiac function characterized by reduced heart rate and ejection fraction (52.5 ± 7.8% vs. 83.9 ± 4.7%) as well as compensatory expansion of left ventricular diameter (4.19 ± 0.19 mm vs. 3.10 ± 0.18 mm). However, there was no maladaptive increase of fibrosis and apoptosis in TG hearts compared to wild type (WT) hearts, and the survival rates also remained the same. The diminution of cardiac contractile function is very likely attributed to a decrease in beta-adrenergic receptor (β-AR) response in TG mice. Importantly, the myocardial infarct size (4.0 ± 1.8% vs. 24.6 ± 3.8%) and apoptotic cell number (1.3 ± 1.0% vs. 5.6 ± 1.5%) induced by ischemia/reperfusion (I/R) injury were significantly attenuated in TG mice. This was associated with decreased expression of inducible cAMP early repressor (ICER) and increased expression of anti-apoptotic protein BCL-2. To further verify the anti-apoptotic effects of PDE3A1, we performed in vitro apoptosis study in isolated adult TG and WT cardiomyocytes. We found that the apoptotic rates stimulated by hypoxia/reoxygenation or H2O2 were indeed significantly reduced in TG myocytes, and the differences between TG and WT myocytes were completely reversed in the presence of the PDE3 inhibitor milrinone. These together indicate that PDE3A1 negatively regulates β-AR signaling and protects against I/R injury by inhibiting cardiomyocyte apoptosis.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular and Cellular Cardiology - Volume 64, November 2013, Pages 11-19
Journal: Journal of Molecular and Cellular Cardiology - Volume 64, November 2013, Pages 11-19
نویسندگان
Masayoshi Oikawa, Meiping Wu, Soyeon Lim, Walter E. Knight, Clint L. Miller, Yujun Cai, Yan Lu, Burns C. Blaxall, Yasuchika Takeishi, Jun-ichi Abe, Chen Yan,