Blockade of NF-kappaB by pyrrolidine dithiocarbamate attenuates myocardial inflammatory response and ventricular dysfunction following coronary microembolization induced by homologous microthrombi in rats.
The objective of this study was to evaluate the effects of specific NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) on inflammatory response and cardiac function in a rat model of coronary microembolization (CME). CME was developed by injecting a suspension of microthrombotic particles (MTPs) into the left ventricle when obstructing the ascending aorta. MTPs were generated from the rat clots sized by filtration through 38 microm screen. Thirty-two Sprague-Dawley rats served as sham group, 128 CME rats were randomized to untreated (CMEU) and PDTC-treated (CMEp) group. Rats in CMEp were administered intraperitoneally with 50, 100, 200 mg kg-1 day-1 PDTC, respectively, from 1 h before to 7 days after operation. The rats were sacrificed on day 1, 3, 7, 14 post-operationally and each subgroup consisted of eight rats. The general morphological characteristics were observed in sections with HE staining, and the severity of myocardial loss (SML) was determined by percent micro-necrotic area in sections with hematoxylin basic fuchsin picric (HBFP) staining 1 day or by percent micro-fibrotic area in sections with Masson's trichrome staining 14 days post-operationally. Left ventricular (LV) function was evaluated echocardiographically and hemodynamically. Activity of NF-kappaB/DNA-binding was analyzed by electrophoresis mobility shift assays (EMSA), and expressions of TNF-alpha, IL-6, and ICAM-1 genes and proteins were detected by Real-time PCR and western blots, respectively. CME rats exhibited pathological changes evidenced by multi-focal myocardial necrosis, inflammatory cell infiltration with remarkably increased SML and persistent reduction of LV function. Activity of NF-kappaB/DNA-binding was markedly increased, also TNF-alpha, IL-6 and ICAM-1 transcripts and their protein expressions were upregulated strongly in the myocardium following CME. PDTC in a dose-dependency significantly suppressed the myocardial inflammatory cytokine transcriptions, decreased SML and improved LV function. Thus, NF-kappaB is markedly activated in CME hearts, and inhibition of NF-kappaB by PDTC prevents the subsequent inflammatory activation and improves cardiac function. Patients with or at risk of CME may benefit from acute anti-inflammatory treatment with PDTC.
Li
Shumei
S
Department of Cardiology, Union Hospital, Fujian Institute of Coronary Artery Disease, Fujian Medical University, Fuzhou, China.
Zhong
Shishun
S
Zeng
Kai
K
Luo
Yukun
Y
Zhang
Feilong
F
Sun
Xudong
X
Chen
Lianglong
L
D000818:Animals; D003328:Coronary Thrombosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013859:Thiocarbamates / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000188:drug therapy
D015850:Interleukin-6; D016328:NF-kappa B; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C020972:pyrrolidine dithiocarbamic acid