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Matrix metalloproteinase inhibition attenuates lv remodeling after myocardial infarction
Aagioteasin II Receptor Blockade By Losartan Reduces The Incidence Of Heart Failure After An MI In Rat, Allen W Davidoff, Mei L. Zhao& HEDJ ter Keurs, University of Calgary, Calgary, Alberta. Cardiac angiotensio II (An) rises transiently in the fust week after coronary artery ligation in the rat. We tested the hypothesis that A&receptor blockade decreases AIi mediited apoptosis, scar area(SC in cm’) and incidence of heart failure at 3months. Methods: LAD ligation in LBN rats caused large MI, was omitted in Sham rats (SH)..Rats received Lossrtan (Li58,086) in tap water, (I& LMI) or not (Mr), for three months starting immediately after recovery tirn surgery. AtIer 3 days or 3 months rats were saeriliced. Lung weight/ body we+ (LW, mg/g) and right ventricle/ body weight (RVW) were calculated in Sham, MI and LMI. Apoptosis in the infarct zone, and in normal remote myocdinm was assessed using DNA ladder& and terminal deoxynucleotidyl transfer&se mediated hiphosphate end labeling (TUNEL). Results: After 3 days, Mi>LMJ hearts showed increased DNA laddtig nod TUNEL positive nuclear labeling, but not in Sham. Myoqte density at end* and subendocardiom of the infarct zone was preserved in LMi as compared to MI. AtIer four months, SC was OM, 2.4kO.13, 1.45M.12, mfxmtsem, LW, 4.0i0.19, 6.5iO.3,8.04f0.34,RVWwas0.51f0.03,1.14iO.09,1.03kO.04,in SH, Mi and LMI, resp. Conclusion: 1) Ml and LMI showed a 2-3 fold increase of LW reflecting frank CHF; incidence of 34% and 4 %, resp. 2) SC and RV hypzrtmphy in LMi was significantly decrea&. 3)Light microscopy suggests reduced myocyte apoptosis of eodo- and subendocardiai myocytes in LMi compared Ml. 4) DNA laddering and TUNEL positive nuclei were observed in MPLMi 5) Decree& SC, and 8-fold reduction in the incidence of heart failure in LMi as compared to MI suggests that immediate early treatment with L158,086 protects against CHF by inhibition of apoptosis.
A26
APOPTOTIC EVENTS DURING LOW-FLOW ISCHRMIA IN THE CANINE MYocARDImi Robert S. Decker, Marlene L. Decker, Sakie Patrick W. Fisher & Francis J. Kiocke. Cardiovascular Research Institute, Northwestern Medical School, Chicago, IL, USA.
Nakamura, Feinberg University
Flow-timction matches and mismatches develop in the canine myocardia following moderate (MLF) and severe (SLF) lowflow ischemia, respectively. Since recent observations report that the contractile dysfuaction which accompanies heart failure may be mediated, in part, by accelerated programmed ceil death, rates of apoptosis were measured during and following low-flow ischemia. Biopsied samples of canine heart were monitored for changes in terminal deoxynucieotidyi transferase (TUNEL) staining, caspase-3 (casp-3) activation and cytochrome-c (cyt-c) release. In sham hearts, 0.03% of the myocytes were TTJNELpositive and disclosed casp3 activation and cyt-c release. During MLF ischemia, no significant change in TUNEL staining could be documented; however, after 2h of repehsion, apoptosis was increased in test tissue (0.47%) but not in remote regions (0.13%). Following SLF &hernia, 0.30% of the myocytes in the test region were TUNEL-positive and revealed q-c release and casp3 activation. In the reperiksed myocardim 0.52% of the myocytes were TUNEL-positive, while 3.7% of the test heart cells displayed activated casp-3 in the absence of both cyt-c release and TUNEL staining. These observations illustrate that the rate of apoptosis is accelerated during and following low-flow ischemia. The presence of casp3-positive/TUNEL negative cells suggests that not ail of the casp-3-activated myocytes are destined to die following SLF. In addition, the evolution of contractile dysfunction may not be correlated with the absolute percentage of apoptotic ceils that are measured at a single point in time.
ENHANCED EXPRESSlON AND ACTlVlTY OF XANTHINE OXIDOREDUCTASE IN FAlUNG HEART Jan W. de JongO, Regien 0. Schoemsker’, Robert de JonaeO, Palmira BemocchP, Eliibeth KeijzeP Roger Hamsod, Hari S. Sharma’ 81 Claudia CeconF. +horaxcenter & ‘Dept of Pharmacol, Erasmus University Rotterdam, NL; ‘Fond S Maugeri Centro di Fisiopatoi Cardiovasc, IRCCS, Gussago, h; ‘Dept of B~oi & Biochem, Univ of Bath, UK.
MATRIX METALLOPROTEINASE INHIBITION AllENUATES LV REMODELING AFTER MYOCARDIAL INFARCTION John A. Delyani, Virginia Casadas, James Campion, Ying Yu, Janet Clawitter, Daniel Becker, Clara Villamil, Gary DeCrescenzo, Paul Vaitkus and Marcia I. Heron. Pharmacia Corporation, Skokie, IL, USA.
The molecular basis for heart failure is unknown, but oxktative stress is associated with the pathogenesis of the diiease. We tested the hypothesis that the activity of xanthine oxkloreductase (XOR), a free-radical generattng enzyme, increases in hypettrophied and failing heart. We studied XOR in two rat models: 1) The monocrotalineinduced right ventricular hyper-trophy and failure model; 2) Coronary artery ligation induced heart failure, with IefI ventricular failure and compensatory right ventricular hypertrophy at diierent stages at 3 and 8 weeks postinfarction, respectively. XOR activity was measured at 30% and the reaction productswere analyzed by HPLC. In both models XOR activity in hypertrophic and control ventricles was similar. In the monocrotaliie model, the hearts showed enhanced XOR activity in the failing right ventricle (65 f 5 mu/g wet wt), as compared to that in the unaffected lefi ventricle (47 + 3 mu/g; P
Matrix metalloproteinases (MMPs) have been implicated in the pathophysiological remodeling occurring after myocardial infarction (Ml). This study determined the post Ml temporal changes of myocardial MMP mRNA expression, gelatinase activity as well as the effect of MMP inhibition on post-Ml remodeling. Rabbits subjected to either permanent coronary artery ligation or sham ligation were treated with the MMP inhibitor SC-77964 or vehicle for 4 weeks. Ventricular geometry and function as well as MMP mRNA expression and gelatinase activity were determined. Following infarction, MMP-2, -13 and -14 mRNA expression were increased at week 1 and remained elevated throughout the study, whereas MMP-1 and 9 transiently increased at week 1 and then returned toward control values. Gelatinase activity within the infarcted myocardium was increased at all time points studied. Lefl ventricular end diastolic area (LVEDA) at week 4 of vehicle treated Ml rabbits increased 25% from baseline (~~0.05) whereas those treated with SC-77964 increased only 10% respectively. Vehicle-treated Ml rabbits had a greater reduction in ejection fraction (EF) than animalstreated with SC-77964 at week 1, and although this beneficial trend continued, EF was not statistically different between the groups at other time points. These data support the hypothesis that inhibition of MMPs is an effective means of abrogating post-Ml remodeling:
A26
APOPTOTIC EVENTS DURING LOW-FLOW ISCHRMIA IN THE CANINE MYocARDImi Robert S. Decker, Marlene L. Decker, Sakie Patrick W. Fisher & Francis J. Kiocke. Cardiovascular Research Institute, Northwestern Medical School, Chicago, IL, USA.
Nakamura, Feinberg University
Flow-timction matches and mismatches develop in the canine myocardia following moderate (MLF) and severe (SLF) lowflow ischemia, respectively. Since recent observations report that the contractile dysfuaction which accompanies heart failure may be mediated, in part, by accelerated programmed ceil death, rates of apoptosis were measured during and following low-flow ischemia. Biopsied samples of canine heart were monitored for changes in terminal deoxynucieotidyi transferase (TUNEL) staining, caspase-3 (casp-3) activation and cytochrome-c (cyt-c) release. In sham hearts, 0.03% of the myocytes were TTJNELpositive and disclosed casp3 activation and cyt-c release. During MLF ischemia, no significant change in TUNEL staining could be documented; however, after 2h of repehsion, apoptosis was increased in test tissue (0.47%) but not in remote regions (0.13%). Following SLF &hernia, 0.30% of the myocytes in the test region were TUNEL-positive and revealed q-c release and casp3 activation. In the reperiksed myocardim 0.52% of the myocytes were TUNEL-positive, while 3.7% of the test heart cells displayed activated casp-3 in the absence of both cyt-c release and TUNEL staining. These observations illustrate that the rate of apoptosis is accelerated during and following low-flow ischemia. The presence of casp3-positive/TUNEL negative cells suggests that not ail of the casp-3-activated myocytes are destined to die following SLF. In addition, the evolution of contractile dysfunction may not be correlated with the absolute percentage of apoptotic ceils that are measured at a single point in time.
ENHANCED EXPRESSlON AND ACTlVlTY OF XANTHINE OXIDOREDUCTASE IN FAlUNG HEART Jan W. de JongO, Regien 0. Schoemsker’, Robert de JonaeO, Palmira BemocchP, Eliibeth KeijzeP Roger Hamsod, Hari S. Sharma’ 81 Claudia CeconF. +horaxcenter & ‘Dept of Pharmacol, Erasmus University Rotterdam, NL; ‘Fond S Maugeri Centro di Fisiopatoi Cardiovasc, IRCCS, Gussago, h; ‘Dept of B~oi & Biochem, Univ of Bath, UK.
MATRIX METALLOPROTEINASE INHIBITION AllENUATES LV REMODELING AFTER MYOCARDIAL INFARCTION John A. Delyani, Virginia Casadas, James Campion, Ying Yu, Janet Clawitter, Daniel Becker, Clara Villamil, Gary DeCrescenzo, Paul Vaitkus and Marcia I. Heron. Pharmacia Corporation, Skokie, IL, USA.
The molecular basis for heart failure is unknown, but oxktative stress is associated with the pathogenesis of the diiease. We tested the hypothesis that the activity of xanthine oxkloreductase (XOR), a free-radical generattng enzyme, increases in hypettrophied and failing heart. We studied XOR in two rat models: 1) The monocrotalineinduced right ventricular hyper-trophy and failure model; 2) Coronary artery ligation induced heart failure, with IefI ventricular failure and compensatory right ventricular hypertrophy at diierent stages at 3 and 8 weeks postinfarction, respectively. XOR activity was measured at 30% and the reaction productswere analyzed by HPLC. In both models XOR activity in hypertrophic and control ventricles was similar. In the monocrotaliie model, the hearts showed enhanced XOR activity in the failing right ventricle (65 f 5 mu/g wet wt), as compared to that in the unaffected lefi ventricle (47 + 3 mu/g; P
Matrix metalloproteinases (MMPs) have been implicated in the pathophysiological remodeling occurring after myocardial infarction (Ml). This study determined the post Ml temporal changes of myocardial MMP mRNA expression, gelatinase activity as well as the effect of MMP inhibition on post-Ml remodeling. Rabbits subjected to either permanent coronary artery ligation or sham ligation were treated with the MMP inhibitor SC-77964 or vehicle for 4 weeks. Ventricular geometry and function as well as MMP mRNA expression and gelatinase activity were determined. Following infarction, MMP-2, -13 and -14 mRNA expression were increased at week 1 and remained elevated throughout the study, whereas MMP-1 and 9 transiently increased at week 1 and then returned toward control values. Gelatinase activity within the infarcted myocardium was increased at all time points studied. Lefl ventricular end diastolic area (LVEDA) at week 4 of vehicle treated Ml rabbits increased 25% from baseline (~~0.05) whereas those treated with SC-77964 increased only 10% respectively. Vehicle-treated Ml rabbits had a greater reduction in ejection fraction (EF) than animalstreated with SC-77964 at week 1, and although this beneficial trend continued, EF was not statistically different between the groups at other time points. These data support the hypothesis that inhibition of MMPs is an effective means of abrogating post-Ml remodeling: