RESUMO
BACKGROUND: A potential mechanism for left ventricular (LV) remodeling after myocardial infarction (MI) is activation of the matrix metalloproteinases (MMPs). This study examined the effects of MMP inhibition (MMPi) on regional LV geometry and MMP levels after MI. METHODS AND RESULTS: In pigs instrumented with radiopaque markers to measure regional myocardial geometry, MI was created by ligating the obtuse marginals of the circumflex artery. In the first study, pigs were randomized to MMPi (n=7; PD166793, 20 mg x kg(-1) x d(-1)) or MI only (n=7) at 5 days after MI, and measurements were performed at 2 weeks. Regional MI areas were equivalent at randomization and were increased in the MI-only group at 2 weeks after MI compared with the MMPi group. In the second study, pigs randomized to MMPi (n=9) or MI only (n=8) were serially followed up for 8 weeks. At 8 weeks after MI, LV end-diastolic dimension was lower with MMPi than in the MI-only group (4.7+/-0.1 versus 5.1+/-0.1 cm, P<0.05). Regional MI area was reduced with MMPi at 8 weeks after MI (1.3+/-0.1 versus 1.7+/-0.1 cm2, P<0.05). MMPi reduced ex vivo MMP proteolytic activity. In the MI region, membrane-type MMP levels were normalized and levels of the endogenous tissue inhibitor of MMPs (TIMP-1) were increased compared with normal levels with MMPi. These effects were not observed in the MI-only group. CONCLUSIONS: MMPi attenuated the degree of post-MI LV dilation and expansion of the infarct during the late phase of MI healing. In addition, exogenous MMPi caused region-specific modulation of certain MMP and TIMP species.
Assuntos
Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/farmacologia , Inibidores de Metaloproteinases de Matriz , Infarto do Miocárdio/enzimologia , Miocárdio/metabolismo , Oligopeptídeos/farmacologia , Animais , Doença Crônica , Dilatação Patológica/prevenção & controle , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/patologia , Suínos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidores Teciduais de Metaloproteinases/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Inibidor Tecidual 4 de MetaloproteinaseRESUMO
BACKGROUND: Global and regional shape changes that occur within the left ventricular wall after myocardial infarction have been termed infarct expansion. A potential mechanism for this postinfarction remodeling is activation of the matrix metalloproteinases. Accordingly, the present study examined the effects of matrix metalloproteinase inhibition on left ventricular global geometry after myocardial infarction in pigs. METHODS: Myocardial infarction was created in pigs by means of occlusion of the first and second obtuse marginal branches of the circumflex coronary artery, resulting in a uniform left ventricular free wall infarct size of 21% +/- 2%. At 5 days after infarction, the pigs were randomized to undergo broad-spectrum matrix metalloproteinase inhibition (n = 9; PD166793, 20 mg. kg(-1). d(-1) by mouth) or myocardial infarction alone (n = 8). Ten pigs served as noninfarction control animals. Left ventricular end-diastolic area, determined by means of echocardiography, was measured 8 weeks after infarction. RESULTS: Left ventricular end-diastolic area increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and myocardial infarction only groups compared to reference control animals (3.7 +/- 0.2 cm(2)), but was reduced with broad-spectrum matrix metalloproteinase inhibition compared to myocardial infarction alone (4.5 +/- 0.2 vs 4.9 +/- 0.2 cm(2), respectively; P <.05). Regional radial stress within the infarct region increased in both infarction groups when compared to values obtained from reference control animals (599 +/- 152 g/cm(2)), but was attenuated in the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition group compared to the myocardial infarction alone group (663 +/- 108 vs 1242 +/- 251 g/cm(2), respectively; P <.05). Similarly, regional myocardial stiffness increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and the myocardial infarction only groups compared with that observed in reference control animals (14 +/- 1 rkm, P <.05) but was lower with broad-spectrum matrix metalloproteinase inhibition than with myocardial infarction alone (42 +/- 6 vs 68 +/- 10 rkm, respectively; P <.05). CONCLUSIONS: Matrix metalloproteinase inhibition reduced postinfarction left ventricular dilation, reduced regional myocardial wall stress, and modified myocardial material properties. These unique findings suggest that increased myocardial matrix metalloproteinase activation after infarction contributes directly to the left ventricular remodeling process.
Assuntos
Modelos Animais de Doenças , Ácidos Hidroxâmicos/uso terapêutico , Inibidores de Metaloproteinases de Matriz , Metaloproteinases da Matriz/fisiologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/enzimologia , Oligopeptídeos/uso terapêutico , Inibidores Teciduais de Metaloproteinases/uso terapêutico , Disfunção Ventricular Esquerda/etiologia , Remodelação Ventricular/efeitos dos fármacos , Análise de Variância , Animais , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Ecocardiografia Transesofagiana , Hemodinâmica/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Oligopeptídeos/farmacologia , Distribuição Aleatória , Volume Sistólico/efeitos dos fármacos , Suínos , Fatores de Tempo , Inibidores Teciduais de Metaloproteinases/farmacologia , Disfunção Ventricular Esquerda/prevenção & controle , Pressão Ventricular/efeitos dos fármacosRESUMO
The cytokine tumor necrosis factor (TNF)-alpha has been causally linked to left ventricular (LV) remodeling, but the molecular basis for this effect is unknown. Matrix metalloproteinases (MMPs) have been implicated in cardiac remodeling and can be regulated by TNF-alpha. This study tested the central hypothesis that administration of a TNF-alpha blocking protein would prevent the induction of MMPs and alter the course of myocardial remodeling in developing LV failure. Adult dogs were randomly assigned to the following groups: 1) chronic pacing (250 beats/min, 28 days, n = 12), 2) chronic pacing with concomitant administration of a TNF-alpha blocking protein (TNF block) using a soluble p75 TNF receptor fusion protein (TNFR:Fc; administered at 0.5 mg/kg twice a week subcutaneously, n = 7), and 3) normal controls (n = 10). LV end-diastolic volume increased from control with chronic pacing (83 +/- 12 vs. 118 +/- 10 ml, P < 0.05) and was reduced with TNF block (97 +/- 9 ml, P < 0.05). MMP zymographic levels (92 kDa, pixels) increased from control with chronic pacing (36,848 +/- 9,593 vs. 87,247 +/- 12,912, P < 0.05) and was normalized by TNF block. Myocardial MMP-9 and MMP-13 levels by immunoblot increased with chronic pacing relative to controls (130 +/- 10% and 118 +/- 6%, P < 0.05) and was normalized by TNF block. These results provide evidence to suggest that TNF-alpha contributes to the myocardial remodeling process in evolving heart failure through the local induction of specific MMPs.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Metaloproteinases da Matriz/metabolismo , Fator de Necrose Tumoral alfa/fisiologia , Função Ventricular Esquerda/fisiologia , Animais , Anticorpos/farmacologia , Modelos Animais de Doenças , Cães , Frequência Cardíaca/fisiologia , Isoenzimas/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/metabolismo , Miocárdio/enzimologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidores Teciduais de Metaloproteinases/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Inibidor Tecidual 4 de MetaloproteinaseRESUMO
BACKGROUND: A cause-effect relationship has been established between matrix metalloproteinases (MMPs) and left ventricular (LV) myocardial remodeling through the use of pharmacologic MMP inhibitors. However, the direct effects of MMP inhibition on MMPs and endogenous tissue inhibitors of metalloproteinases (TIMPs) in LV human myocardial fibroblasts (LVHMFs) remain unknown. This study measured MMP-2, MMP-9, MMP-13, MT1-MMP, and TIMP-1 release in LVHMFs. METHODS AND RESULTS: LVHMF cultures were established from six individual patients (passages 2-5) and incubated with and without the broad-spectrum MMP inhibitor PD166793 (100 microM) for 12-36 h. While PD166793 did not influence MMP-2 release, MMP-9 levels based on substrate zymography increased at 36 h by over 30% (P < 0.05). TIMP-1 levels increased in a time-dependent manner with no effect from PD166793 incubation. However, the MMP-9/TIMP-1 ratio was increased by over 20% from time-matched values following 12-36 h of exposure to PD166793 (P < 0.05). Similar results obtained after incubation of LVHMF cultures with the broad-spectrum MMP inhibitor Batimastat (BB-94) suggest that these observations are due to a general class effect of broad-spectrum MMP inhibitors. CONCLUSIONS: This study is the first to demonstrate that a selective induction and release of an MMP species occurs with sustained exposure to pharmacologic MMP inhibition in LVHMFs. These observations may have particular importance with respect to controlling this proteolytic system in the context of LV myocardial remodeling.