Attenuation of increased myocardial ischaemia-reperfusion injury conferred by hypercholesterolaemia through pharmacological inhibition of the caspase-1 cascade.
1. Hypercholesterolaemia has been shown to be associated with greater myocardial ischaemia-reperfusion injury, in which apoptosis and inflammation-mediated necrosis both play a key role. 2. Caspase-1 is involved in the activation of both apoptosis and inflammation, through the intermediate of interleukin-1beta (IL-1beta). We herein examined whether pharmacological inhibition of the caspase-1 cascade, using Ac-Tyr-Val-Ala-Asp-CH(2)Cl (Ac-YVAD.cmk), after myocardial ischaemia have greater protective effects on myocardial ischaemia-reperfusion injury in diet-induced hypercholesterolaemic rabbits. 3. Male rabbits fed with standard chow or chow supplemented with 0.5% cholesterol and 10% coconut oil for 8 weeks were subjected to 30 min of left circumflex artery occlusion followed by 4 h of reperfusion. An intravenous bolus of Ac-YVAD.cmk (1.6 mg kg(-1)) or vehicle was given 20 min after coronary occlusion. 4. Postischaemic administration of Ac-YVAD.cmk markedly decreased infarct size from 26+/-3% to 12+/-2% in normally fed rabbits (P=0.005) and from 41+/-6% to 14+/-2% in cholesterol-fed rabbits (P<0.001). 5. In the ischaemic non-necrotic area, treatment with Ac-YVAD.cmk markedly reduced the percentage of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL)-positive cardiomyocytes from 15.5+/-0.8% to 2.2+/-0.1% in normally fed rabbits (P<0.001) and from 39.0+/-2.3% to 2.2+/-0.1% in cholesterol-fed rabbits (P<0.001). 6. Ac-YVAD.cmk treatment resulted in a reduction not only of IL-1beta and caspase-1, but also of caspase-3 in the ischaemic myocardium in both normally fed and cholesterol-fed rabbits. 7. No differences in infarct size, the percentage of TUNEL-positive cardiomyocytes, IL-1beta levels or activity of caspase-1 and caspase-3 were observed between Ac-YVAD.cmk-treated normally fed and cholesterol-fed rabbits. 8. This study demonstrates that injection of a selective caspase-1 inhibitor after myocardial ischaemia markedly reduced the detrimental effect conferred by hypercholesterolaemia on myocardial ischaemia-reperfusion injury by attenuating both necrotic as well as apoptotic cell death pathways through inhibition of IL-1beta production and activation of caspase-1 and caspase-3.
Wang
Tzung-Dau
TD
Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan, Republic of China.
Chen
Wen-Jone
WJ
Mau
Tzan-Jr
TJ
Lin
Jong-Wei
JW
Lin
Wan-Wan
WW
Lee
Yuan-Teh
YT
D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D002791:Cholesterol, Dietary / Q000009:adverse effects / Q000097:blood; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology*; D011817:Rabbits; D015843:Serpins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014764:Viral Proteins
D061945:Caspase Inhibitors; D002791:Cholesterol, Dietary; D015853:Cysteine Proteinase Inhibitors; D015843:Serpins; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; D020170:Caspase 1