Adenosine A₃ receptor-mediated cardioprotection against doxorubicin-induced mitochondrial damage

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• 作者：Avishag K. Emanuelov ; Asher Shainberg ; Yelena Chepurko ; Doron Kaplan ; Alex Sagie ; Eyal Porat ; Michael Arad ; Edith Hochhauser
• 关键词：A₃ adenosine receptors ; Ca²⁺ homeostasis ; Cl-IB-MECA ; Doxorubicin
• 刊名：Biochemical Pharmacology
• 出版年：2010
• 出版时间：15 January 2010
• 年：2010
• 卷：79
• 期：2
• 页码：180-187
• 全文大小：433 K

文摘

Cardiotoxicity associated with doxorubicin (DOX) treatment limits the therapeutic efficiency of this drug against cancer. 2-Chloro-N(6)-(3-iodobenzyl)adenosine-5′-N-methyluronamide (Cl-IB-MECA), a selective agonist of A₃ adenosine receptor (A₃R), reduces DOX toxicity in newborn rat cultured cardiomyocytes. The study's aim was to determine whether the protection demonstrated by Cl-IB-MECA attenuates cardiac depression in vivo. In addition, we wished to examine whether this protective pathway affects the sarcoplasmic reticulum (SR) calcium uptake and release, as well as intramitochondrial Ca²⁺ accumulation induced by DOX.

Rats were injected every alternate day (6 times) with (1) saline, (2) 2.5 mg/kg i.p. DOX, (3) 33 μg/kg i.v. Cl-IB-MECA, (4) DOX + Cl-IB-MECA. Left ventricular functions were assessed by invasive (pressure) and non-invasive (echocardiography) techniques at the end of the injection period and 4 weeks later. Cytosolic and intramitochondrial calcium levels were measured with indo-1 and rhod-2 probes. SR Ca²⁺ content was determined by exposing cultured rat cardiomyocytes to caffeine.

Echocardiography data demonstrate left ventricular wall thinning (23 % ), an increase in the end systolic dimension (170 % ) and decreased fractional shortening (35 ± 5 % vs. 54 ± 5 % , p < 0.01) in DOX-treated animals, compared to the control group. DOX increased Ca²⁺ levels in the cytosol and in mitochondria by diminishing the SR Ca²⁺ uptake. Pretreatment with Cl-IB-MECA attenuated left ventricular dysfunction, improved SR calcium storage capacity and prevented mitochondrial Ca²⁺ overload.

We conclude that the adenosine A₃ receptor agonist is effective in vivo against DOX cardiotoxicity via the restoration of Ca²⁺ homeostasis and prevention of mitochondrial damage that occurs as a result of Ca²⁺ overload.