S1P lyase: a novel therapeutic target for ischemia-reperfusion injury of the heart.

نویسندگان

  • Padmavathi Bandhuvula
  • Norman Honbo
  • Guan-Ying Wang
  • Zhu-Qiu Jin
  • Henrik Fyrst
  • Meng Zhang
  • Alexander D Borowsky
  • Lisa Dillard
  • Joel S Karliner
  • Julie D Saba
چکیده

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that promotes cardiomyocyte survival and contributes to ischemic preconditioning. S1P lyase (SPL) is a stress-activated enzyme responsible for irreversible S1P catabolism. We hypothesized that SPL contributes to oxidative stress by depleting S1P pools available for cardioprotective signaling. Accordingly, we evaluated SPL inhibition as a strategy for reducing cardiac ischemia-reperfusion (I/R) injury. We measured SPL expression and enzyme activity in murine hearts. Basal SPL activity was low in wild-type cardiac tissue but was activated in response to 50 min of ischemia (n = 5, P < 0.01). Hearts of heterozygous SPL knockout mice exhibited reduced SPL activity, elevated S1P levels, smaller infarct size, and increased functional recovery after I/R compared with littermate controls (n = 5, P < 0.01). The small molecule tetrahydroxybutylimidazole (THI) is a Federal Drug Administration-approved food additive that inhibits SPL. When given overnight at 25 mg/l in drinking water, THI raised S1P levels and reduced SPL activity (n = 5, P < 0.01). THI reduced infarct size and enhanced hemodynamic recovery in response to 50 min of ischemia and to 40 min of reperfusion in ex vivo hearts (n = 7, P < .01). These data correlated with an increase in MAP kinase-interacting serine/threonine kinase 1, eukaryotic translation initiation factor 4E, and ribosomal protein S6 phosphorylation levels after I/R, suggesting that SPL inhibition enhances protein translation. Pretreatment with an S1P₁ and S1P₃ receptor antagonist partially reversed the effects of THI. These results reveal, for the first time, that SPL is an ischemia-induced enzyme that can be targeted as a novel strategy for preventing cardiac I/R injury.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Effects of normobaric hyperoxia pretreatment on ischemia-reperfusion injury in regional ischemia model of isolated rat heart

Abstract Introduction: Resent studies have been shown beneficial effects of hyperoxia pretreatment against ischemia-reperfusion injury in different organs. The aim of the present study was to investigate early and late effects of normobaric hyperoxia (≥95% O2) pretreatment on ischemia-reperfusion injuries in isolated rat hearts. Methods: Following 60 and 180 minutes of hyperoxia, rat hearts w...

متن کامل

Therapeutic effects of 1,25-dihydroxyvitamin D and losartan co-administration on myocardial ischemia-reperfusion injury in rats

Introduction: Studies support the idea that low levels of vitamin D are associated with a higher risk of heart disease. Losartan has also been prescribed as a drug commonly used for treating hypertension. The aim of the current study was to investigate the effects of 1,25-dihydroxyvitamin D in combination with a non-hypotensive dose of losartan on myocardial infarct size, reperfusion-induced...

متن کامل

Potential therapeutic effect of pomegranate seed oil on ovarian ischemia/reperfusion injury in rats

Objective(s): The aim of this study is to determine the therapeutic effects of pomegranate seed oil, which is a powerful antioxidant and anti-inflammatory agent, on ovarian-ischemia and reperfusion injury in rats.Materials and Methods: Fifty-six  female albino Wistar rats were divided into 7 equal groups. Group 1; Sham Operation, Group 2; Ischemia, Group 3; Ischemia + Reperfusion, Group 4; Isch...

متن کامل

Cardioprotective effect of aqueous extract of Chichorium intybus L. on ischemia-reperfusion injury in isolated rat heart

Objective: Several studies have shown that Chichorium intybus L. (C. intybus) which possesses flavonoid compounds has an effective role in treatment of cardiovascular diseases. Contractile dysfunction mostly occurs after acute myocardial infarction, cardiac bypass surgery, heart transplantation and coronary angioplasty. The aim of the present study was to investigate the effect of aqueous extra...

متن کامل

Orexin-A Improves Hepatic Injury Following Renal Ischemia Reperfusion in Rats

Introduction: Orexins are novel neuropeptides that are localized in neurons in the lateral hypothalamus. They are implicated in a wide variety of physiological functions. Orexin peptides and receptors are found in many peripheral organs such as kidneys. It has been demonstrated that exogenous orexin-A can induce protective effects against ischemia–reperfusion injury in many organs. The goal ...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • American journal of physiology. Heart and circulatory physiology

دوره 300 5  شماره 

صفحات  -

تاریخ انتشار 2011