Abstract
To evaluate whether chronic cocaine abuse will increase cardiac Fas-dependent and mitochondria-dependent apoptotic pathways, thirty-two male Wistar rats at 3–4 months of age were randomly divided into a vehicle-treated group (phosphate-buffered saline, PBS, 0.5 mL, SQ per day) and a cocaine-treated group (Cocaine, 10 mg/kg, SQ per day). After 3 months of treatment, the excised left ventricles were measured by H&E staining, Western blotting, DAPI staining and TUNEL assays. More cardiac TUNEL-positive apoptotic cells were observed in the Cocaine group than the PBS group. Protein levels of TNF-alpha, Fas ligand, Fas death receptor, FADD, activated caspase-8, and activated caspase-3 (Fas-dependent apoptosis) extracted from excised hearts in the Cocaine group were significantly increased, compared to the PBS group. Protein levels of cardiac Bax, cytosolic cytochrome c, t-Bid-to-Bid, Bak-to-Bcl-xL, Bax-to-Bcl-2 ratio, activated caspase-9, and activated caspase-3 (mitochondria-dependent apoptosis) were significantly increased in the Cocaine group, compared to the PBS group. Chronic cocaine exposure appeared to activate the cardiac Fas-dependent and mitochondria-dependent apoptosis, which may indicate a possible mechanism for the development of cardiac abnormalities in humans with chronic cocaine abuse.
Highlights
cocaine exposure (Cocaine) is the most commonly used illicit drug in the world
phosphate buffered saline (PBS), Wistar rats with PBS exposure; Cocaine, Wistar rats with cocaine exposure; No significant difference between PBS and Cocaine groups
To further understand the cardiac Bcl-2 family in the mitochondria-dependent apoptotic pathway in the Cocaine group, we examined the protein levels of the Bcl-2 family (Bcl-xL, Bak, Bcl-2, Bax, Bcl-2–associated death promoter (Bad)) and cytosolic cytochrome c in the excised hearts of both the PBS and Cocaine groups by Western blotting
Summary
Cocaine is the most commonly used illicit drug in the world. Cardiovascular complications related to cocaine abuse include myocardial ischemia, infarction, inflammation, rhythm disturbances, aortic dissection and sudden cardiac death [1,2,3,4]. The Fas-dependent apoptotic pathway is believed to be one of the major pathways directly triggering cardiac apoptosis [9,14,15]. Pro-apoptotic and anti-apoptotic Bcl-2 family members can homodimerize or heterodimerize to each other, and appear to interact with and neutralize each other, so that the relative balance of these effectors strongly influences cytochrome c release and cell fate [19]. Caspase-8 can cleave Bid (Bcl-2 homology domain 3 (BH3) interacting domain death agonist) into truncate Bid (t-Bid), cause the release of mitochondrial cytochrome c, leading to the activation of caspase-9, which can activate caspase-3 [14,21,22]. Previous studies have suggested that cocaine-induced apoptosis in cardiomyocytes is mediated only by the mitochondria-dependent pathway in the cell line [1,3]. We hypothesized that chronic cocaine exposure in rats may predispose them to greater levels of activated cardiac Fas-dependent and mitochondria-dependent apoptosis
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