Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose.
Recent studies have demonstrated the cardioprotective abilities of resveratrol, a polyphenolic antioxidant present in red wine. Resveratrol can also kill cancer cells at relatively higher doses by exerting a death signal. We reasoned that resveratrol might possess the ability to protect the cells at lower doses as observed during pharmacological preconditioning of the heart, while at higher doses cause cell death as found for cancer cells. To test this hypothesis, rats were randomly fed for 14 days by gavaging any of the four doses of resveratrol - 2.5, 5.0, 25 or 50 mg/kg - while vehicle-fed animals served as placebo control. After 14 days, isolated working hearts were prepared from both experimental and control animals, and the hearts were subjected to 30-min global ischemia followed by 2 h of reperfusion. The rats fed either 2.5 or 5 mg/kg dose of resveratrol for 14 days provided cardioprotection as evidenced by improved post-ischemic ventricular recovery and reduction of myocardial infarct size and cardiomyocyte apoptosis compared to control. In contrast, the hearts fed either 25 or 50 mg/kg dose of resveratrol depressed cardiac function and increased myocardial infarct size and number of apoptotic cells. The results for Western blots and RT-PCR demonstrated an increase of protein and RNA transcripts of redox proteins including thioredoxin (Trx)-1, Trx-2, glutaredoxin (Grx)-1, Grx-2, redox factor Ref-1 as well as redox-sensitive transcription factor NFkappaB, and survival factors such as phosphorylated-Akt (p-Akt), and Bcl-2 in the animals fed lower doses (2.5 and 5 mg/kg) of resveratrol, while the reverse was true for the animals fed higher doses (25 and 50 mg/kg) of resveratrol. The results thus indicate that at lower doses (2.5 or 5 mg/kg), resveratrol exerts survival signal by up-regulating anti-apoptotic and redox proteins Akt and Bcl-2, while at higher doses (>25 mg/kg), it potentiates a death signal by down-regulating redox proteins and up-regulating pro-apoptotic proteins.
Dudley
Jocelyn
J
Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA.
Das
Samarjit
S
Mukherjee
Subhendu
S
Das
Dipak K
DK
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D012717:Sesquiterpenes; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D013729:Terpenes / Q000494:pharmacology*; D014920:Wine; D000094162:Phytoalexins
D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D012717:Sesquiterpenes; D013267:Stilbenes; D013729:Terpenes; D000077185:Resveratrol; D000094162:Phytoalexins