Differences in inflammation, MMP activation and collagen damage account for gender difference in murine cardiac rupture following myocardial infarction

Cardiac rupture remains a fatal complication of acute myocardial infarction (MI) with its mechanism partially understood. We hypothesized that damage to the collagen matrix of infarcted myocardium is the central mechanism of rupture and therefore responsible for the difference in the incidence of rupture between genders. We examined left ventricular (LV) remodeling during the acute phase post-MI in 129sv mice. Following induction of MI, we monitored rupture events and assessed the extent of LV remodeling by echocardiography. Muscle tensile strength, content of insoluble and soluble collagen, expression and activity of matrix metalloproteinases (MMPs) and density of inflammatory cells were determined in the infarcted and non-infarcted myocardium. We then tested the effects of MMP inhibition on rupture. Compared to female mice, males with MI displayed greater extent of LV remodeling, reduced muscle tensile strength, loss of insoluble collagen, local inflammatory response and MMP-9 activation, changes associated with a 3 times higher incidence of rupture than in females. MMP-9 expression by circulating blood mononuclear cells was also increased in male mice with acute MI. Treatment of male mice with an MMP inhibitor reduced MMP activity and halved rupture incidence. Our findings demonstrate that the differences in the severity of inflammation, MMP activation and damage to collagen matrix account for gender difference in cardiac rupture. Our study illustrates the breakdown of fibril collagen as a central mechanism of cardiac rupture.     

基质金属蛋白酶及抑制剂在心肌梗死后心室重构中的作用

目的　研究大鼠心肌梗死后外源性基质金属蛋白酶抑制剂 (多西环素 ,Doxycycline)在心室重构中的作用。方法　 70只SD大鼠随机分为对照组 (10只 )、手术对照组 (9只 )、心肌梗死后 1天组 (10只 )、心肌梗死后 1周组 (10只 )、心肌梗死后 2周组 (8只 )、心肌梗死后 4周组 (7只 )、治疗 2周组 (8只 )和治疗 4周组 (8只 ) ,采用免疫组织化学、酶谱法、免疫印迹 (WesternBlotting)、逆转录 聚合酶链反应 (RT PCR)和AcusonSequoia 5 12超声心动图仪分别测定胶原含量 ,Ⅰ Ⅲ胶原比例、基质金属蛋白酶 2 ,9(MMP 2 ,9)蛋白和mRNA的变化规律及心功能。结果　多西环素治疗后 ,胶原含量明显减少 ,Ⅰ Ⅲ胶原比例下降得以改善 (P <0 .0 5 ) ,MMP 2 ,9蛋白和mRNA在心肌梗死后活性减少 ,基质金属蛋白酶组织抑制剂 1蛋白含量和mRNA转录无明显变化 ,治疗组心功能在术后 4周得以改善。结论　多西环素治疗后MMP 2 ,9的mRNA转录减少 ,MMP 2 ,9活性降低 ,胶原含量减少 ,Ⅰ Ⅲ胶原比例恢复 ,这些影响可能是其改善心肌梗死后心室重构的机制之一。     

Phosphatase PTEN is critically involved in post-myocardial infarction remodeling through the Akt/interleukin-10 signaling pathway

The inflammatory cytokines interleukin (IL)-10 and tumor necrosis factor (TNF)-α play an important role in left ventricular (LV) remodeling after myocardial infarction (MI). Phosphatase and tensin homolog deleted on chromosome ten (PTEN) inactivates protein kinase Akt and promotes cell death in the heart. However, it is not known whether PTEN promotes post-MI remodeling by regulating IL-10 and TNF-α. MI was induced in wild-type (WT) mice and Pten heterozygous mutant (HET) mice. Pten adenoviruses (adPten) or empty vectors (adNull) were injected into the peri-infarct area of WT mice. LV dilation was attenuated and fractional shortening was increased in HET mice compared to WT mice. Survival rate and fractional shortening were decreased in adPten mice compared to adNull mice. Leukocyte infiltration into the peri-infarct area was attenuated in HET mice and worsened in adPten mice. PTEN expression was upregulated in the infarcted heart of WT mice. Partial inactivation of PTEN increased the production of IL-10 and decreased the expression of TNF-α and matrix metalloproteinase (MMP)-2 and -9 after MI in HET mice. PTEN overexpression caused opposite effects in the infarcted heart. Moreover in the infarcted heart of HET mice, Akt inhibition decreased Stat3 phosphorylation and IL-10 expression, and blockade of the IL-10 receptor increased TNF-α and MMP-2 expression. Both Akt inhibition and IL-10 receptor blockade abolished the attenuation of post-MI remodeling in HET mice. In conclusion, PTEN is critically involved in post-MI remodeling through the Akt/IL-10 signaling pathway. Therefore, targeting PTEN may be an effective approach to post-MI remodeling.     

白藜芦醇对糖尿病大鼠心肌缺血再灌注损伤时炎性反应的影响

目的研究白藜芦醇预处理对糖尿病大鼠心肌缺血再灌注损伤的作用,以及对炎性反应的影响。 方法取糖尿病模型制备成功的SD大鼠30只,采用随机数字表法分为3组（n=10）：假手术组（Sham组）、心肌缺血再灌注组（MI/R组）和心肌缺血再灌注+白藜芦醇组（MI/R+Res组）。B超测量左心室的射血分数（LVEF）以及左室短轴缩短率（FS）,于再灌注末时处死5只大鼠,用TTC染色法测定心肌梗死面积,另再处死5只大鼠,经腹主动脉取血测心肌损伤标志物乳酸脱氢酶（LDH）和肌酸激酶同工酶（CK-MB）的浓度,采用ELISA法检测血清的肿瘤坏死因子-α（TNF-α）,白介素-6（IL-6）,细胞间黏附分子-1（ICAM-1）,并取心肌组织,通过RT-PCR法测TNF-α,IL-6,基质金属蛋白酶-9（MMP-9）的含量。 结果与Sham组比较,MI/R组与MI/R+Res组的LDH和CK-MB浓度,血清TNF-α,IL-6,ICAM-1含量以及心肌梗死面积均显著增高,LVEF和FS显著降低,心肌TNF-α,IL-6,MMP-9的mRNA表达增加（均P<0.05）;与MI/R组比较,MI/R+Res组的LDH和CK-MB浓度,血清TNF-α,IL-6,ICAM-1含量以及心肌梗死面积均显著降低,LVEF和FS显著升高,TNF-α,IL-6,MMP-9的mRNA表达减少（均P<0.05）。 结论白藜芦醇预处理可以减轻糖尿病大鼠心肌缺血再灌注损伤时的炎性反应。     

L和L/T型钙通道对急性梗死心肌肌腱蛋白的调节

目的:研究L和L/T型钙通道对梗死心肌基质金属蛋白酶(MMP-2、MMP-3、MMP-9)及细胞外间基质肌腱蛋白(tenascin-c,TN-C)的影响。方法:结扎大鼠左冠状动脉建立心肌梗死模型,术前7d分别用安慰剂、L型钙通道阻滞剂阿莫地平(4mg·kg-1.d-1)、L/T型钙通道阻滞剂米贝拉地尔(10mg·kg-1.d-1)。术后1d、3d、7d分别检测左心室游离壁(left ventricular free wall,LVFW)MMP-2、MMP-3及MMP-9蛋白表达;免疫荧光检测LVFW心肌TN-C的分布。结果:术前LVFW心肌排列基本正常,术后7dLVFW心肌有不同程度的坏死、肥厚及纤维化。术后1d、3d、7dLVFWMMP-2、MMP-3、MMP-9及TN-C蛋白表达一直处于高水平,各时相点与基础值相比差异有显著性(P<0.01)。米贝拉地尔更明显地抑制LVFWMMP-2、MMP-3、MMP-9及TN-C上调,缩小心肌梗死病灶,阿莫地平能抑制MMP-2、MMP-3、MMP-9及TN-C上调,但较米贝拉地尔弱。结论:心肌梗死病理过程中,梗死病灶内MMP-2、MMP-3、MMP-9及TN-C上调,L和L/T型钙通道阻滞剂能减轻心肌重构与选择性的抑制心肌组织中的MMP-2、MMP-3、MMP-9及TN-C表达有关。     

Echocardiography-derived left ventricular end-systolic regional wall stress and matrix remodeling after experimental myocardial infarction

OBJECTIVES: We tested the hypothesis that regional end-systolic left ventricular (ESLV) wall stress is associated with extracellular matrix remodeling activity after myocardial infarction (MI). BACKGROUND: Increased left ventricular (LV) wall stress is a stimulus for LV enlargement, and echocardiography can be used to estimate regional wall stress. A powerful validation of a noninvasive method of estimating wall stress would be predicting cellular responses after a MI. METHODS: Echocardiographic images were obtained in rats 1, 7, 14 or 21 days after coronary ligation (n = 11) or sham surgery (n = 5). End-systolic left ventricular wall stress was calculated by finite element analysis in three regions (infarcted, noninfarcted and border) from short-axis images. Matrix metalloproteinase-9 (MMP-9) and macrophage density were determined by immunohistochemistry, and positive cells were counted in high power fields (hpf). RESULTS: Average ESLV wall stress was higher in rats with MI when compared to shams irrespective of time point (p < 0.01), and ESLV wall stress in the infarcted regions increased with time (25.1 +/- 5.9 vs. 69.9 +/- 4.4 kdyn/cm2, day 1 vs. 21; p < 0.01). Matrix metalloproteinase-9 expression was higher in infarcted and border regions when compared to noninfarcted regions (22.1 vs. 25.7 vs. 0.10 cells/hpf, respectively; p < 0.01). Over all regions, ESLV wall stress was associated with MMP-9 (r = 0.76; p < 0.001), macrophage density (r = 0.72; p < 0.001) and collagen content (r = 0.67; p < 0.001). End-systolic left ventricular wall stress was significantly higher when MMP-9 positive cell density was greater than 10 cells/hpf (45+/-20 vs. 14+/-10 kdyn/cm2; p < 0.001). CONCLUSIONS: Regional increases in ESLV wall stress determined by echocardiography-based structural analysis are associated with extracellular matrix degradation activity.     

缺血时间对大鼠心肌缺血再灌注损伤及基质金属蛋白酶表达的影响

目的 观察不同缺血时间对大鼠心肌缺血再灌注损伤的影响并探讨其可能机制.方法 雄性SD大鼠24只,采用完全随机法分为心肌缺血30 min后再灌注组(A组,8只),心肌缺血10 min后再灌注组(B组,8只),假手术组(C组,8只).采用组织病理学检查和超声心动图检测评价3组大鼠心肌损伤、心脏功能及心室重构情况,并采用RT...     

白细胞介素-10对急性心肌梗死后细胞外基质重构影响的实验研究

目的 观察白细胞介素-10(IL-10)对大鼠急性心肌梗死后心肌基质金属蛋白酶(MMP)-2、9,金属蛋白酶组织抑制因子(TIMP)-1表达及胶原代谢的作用,探讨其对急性心肌梗死后心肌基质重构的影响.方法 18只大鼠随机分为假手术组、MI/AAV2转染组作为对照和MI/AAV2-IL-10转染组,每组6只.结扎大鼠左冠状动脉前降支建立急性心肌梗死动物模型,同时应用基因重组2型腺相关病毒(AAV-2)携带IL-10基因转染心肌组织.RT-PCR和ELISA观察心肌IL-10 mRNA和蛋白的表达.逆转录聚合酶链反应、免疫印迹法、明胶酶谱、免疫组化检测转染后心肌组织表达MMP-2、9,TIMP-1,Ⅰ、Ⅲ型胶原水平的变化.结果 心肌梗死5 d后,MI/AAV2-IL-10组检测到IL-10 mRNA和蛋白的表达;MI/AAV2组较假手术组心肌MMP-2、9,Ⅰ、Ⅲ型胶原表达明显升高;而MI/AAV2-IL-10组较MI/AAV2组梗死心肌各部位MMP-2、9表达减少,TIMP-1表达升高,其中,梗死边缘区的MMP-2表达降低14.6%(P＜0.01),MMP-9降低24.7%(P＜0.01),TIMP-1升高73.1%(P＜0.01),Ⅰ、Ⅲ型胶原表达分别下降了47.6%(P＜0.01)、23.6%(P＜0.05),Ⅰ/Ⅲ型胶原比值下降.结论 IL-10通过对MMP/TIMP的作用,改善大鼠急性心肌梗死后心肌胶原沉积和组织重构.     

Induction of matrix metalloproteinase-9 and -3 in nonsteroidal anti-inflammatory drug-induced acute gastric ulcers in mice: regulation by melatonin

Abstract:  The pathogenesis of gastric ulcer is associated with remodeling of extracellular matrix (ECM) by various matrix metalloproteinases (MMPs). However, how MMPs are regulated during nonsteroidal anti-inflammatory drug (NSAID)-induced acute gastric ulceration is not well studied. In this study, different NSAIDs (80 mg/kg b.w.) were applied to generate acute gastric ulcer in the BALB/c mouse and the regulation of MMPs were investigated. NSAIDs caused dose-dependent induction in MMP-9 and -3 activities and expressions in ulcerated gastric tissues along with significant infiltration of inflammatory cells and disruption of gastric mucosal layer. In addition, an increase in tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-8 expression, excessive generation of hydroxyl radical (^•OH), and protein oxidation and lipid peroxidation were observed in acute ulcerated gastric tissues. In this study, the efficacy of melatonin on activities of MMP-9 and -3 during prevention of gastric ulcers was tested. Melatonin at a dose of 60 mg/kg b.w. downregulated MMP-9 and -3 both at the enzyme and protein levels in mouse gastric tissues during prevention as well as healing of acute gastric ulcers. It also blocked oxidative stress via inhibition of protein oxidation, lipid peroxidation, ^•OH generation and SOD-2 expression. Moreover, it suppressed myeloperoxidase activity and expressions of TNF-α, IL-1β and IL-8. This study documents for the first time that induction of MMP-9 and -3 activities accompany NSAID-induced inflammation and oxidative stress in gastric tissues and indicates that, melatonin may be a preventive or therapeutic remedy for gastric ulcers.     

脑钠肽静脉滴注抑制大鼠心肌梗死后的心室重构

目的验证和比较持续静脉滴注外源性脑钠肽（BNP）和依那普利灌胃对于心肌梗死后心室重构的抑制作用,并观察其对心肌基质金属蛋白酶（MMPs）的影响。方法 SD大鼠随机分为4组：假手术组;对照组;心肌梗死＋依那普利[10mg/（kg·d）]灌胃治疗组;心肌梗死＋脑钠肽[0.06μg/（kg·min）]持续静脉微泵推注治疗组。应用超声心动图、免疫组化、ELISA和Western blot等方法评估各组的心室重构和心功能状况。结果 BNP和依那普利可抑制大鼠心肌梗死后左室质量指数的增加（分别减少13.2%和16.9%,P〈0.05）,改善心肌梗死后大鼠的左室舒张未压（分别降低33.0%和45.8%,P〈0.05）。超声心动图结果提示,给予BNP和依那普利持续治疗28天后,其左室舒张末径（LVEDD）大小和左室短轴收缩率（FS）优于对照组[LVEDD：对照组（8.8±0.6）mm,依那普利组（7.5±0.7）mm,脑钠肽组（7.5±1.0）mm,P〈0.05;FS：对照组（19.2±2.6）%,依那普利组（27.7±5.6）%,脑钠肽组（27.5±3.9）%,P〈0.05]。依那普利和BNP都能够明显抑制心肌梗死后期非梗死区的胶原、特别是Ⅰ型胶原的增生[对照组（6.8±1.4）%,依那普利组（4.0±0.9）%,脑钠肽组（3.7±1.1）%;P〈0.05]。静脉输注BNP治疗可升高心肌的cGMP含量,但抑制心肌血管紧张素Ⅱ的作用不及依那普利。BNP对非梗死区MMP-2和MMP-9含量无明月显影响。结论心肌梗死后持续静脉给予BNP可能通过cGMP介导的信号途径发挥其心脏保护作用,包括抑制心肌梗死后的心脏肥厚、心室扩大,改善心功能,减少非梗死区心肌胶原沉积,对非梗死区MMP-2和MMP-9的表达并无明显影响。     

Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis

Calcific aortic valve stenosis (AS), the main heart valve disease in the elderly, is characterized by extensive remodeling of the extracellular matrix. Matrix metalloproteinases (MMPs) are upregulated in calcific AS and might modulate matrix remodeling. The regulatory mechanisms are unclear. As recent studies have suggested that calcific AS might result from an inflammatory process involving leukocyte invasion and activation, the present study aimed to elucidate the role of the pro-inflammatory cytokine interleukin (IL)-1β on MMP expression and cell proliferation in human aortic valves. Immunohistochemistry for leukocytes, IL-1β and MMP-1 was performed on aortic valves with (n=6) and without (n=6) calcification obtained at valve replacement or autopsy. Stenotic valves showed marked leukocyte infiltration and associated expression of IL-1β and MMP-1. In control valves only scattered leukocytes, low staining for MMP-1 and no staining for IL-1β were present. Double-label immunostaining localized IL-1β expression mainly to leukocytes and MMP-1 expression to myofibroblasts. Stimulation of cultured human aortic valve myofibroblasts with IL-1β lead to a time-dependently increased expression of MMP-1 and MMP-2 by Western blotting and zymography, whereas MMP-9 remained unchanged. Cell proliferation was increased by IL-1β as determined by bromodesoxyuridine incorporation. Thus, IL-1β may regulate remodeling of the extracellular matrix in calcific AS.     

MMPs与早期行PCI的NSTEMI患者左室重构相关

目的: 探讨早期行冠状动脉介入治疗（PCI）的非ST段抬高型心肌梗死（NSTEMI）患者血浆中金属基质蛋白酶（MMPs）的时间变化规律及与心肌梗死（MI）后左心室重构的相关性。方法: 成功随访12个月的早期行PCI的NSTEMI患者126例,于入院即刻、发病后2 d、4 d、2周、4周抽取外周静脉血,ELISA检测血浆中MMP-2和MMP-9的浓度。PCI术后患者临床随访12个月,对比入院时及术后12个月心脏超声图,分析左室舒张末期容积（LVEDV）和左室射血分数（LVEF）的变化及与MMPs的相关关系。结果: ① MI后2周的时间内,血浆中MMP-2的浓度随着MI时间的延长而不断升高,其后MMP-2的浓度开始下降;MMP-9的浓度在MI后4 d时达到最高,其后MMP-9浓度开始明显下降。②同入院时相比,MI后12个月后LVEDV明显扩大,完成随访的患者LVEDV扩大(11±4) ml。LVEF明显降低,降低(9±3)%。 MI后2 d时的MMP-9的浓度与ΔLVEDV呈正相关,与ΔLVEF的相关关系不明显。4 d时的MMP-9值与12个月后的ΔLVEDV和ΔLVEF呈正相关;MI后2周和4周MMP-2的浓度与12个月后的ΔLVEDV和ΔLVEF呈正相关。结论: NSTEMI患者MI后4 d的MMP-9和2周的MMP-2浓度与短期内左心室重构及左心室功能具有明显相关性。     

Infarct Size Reduction and Attenuation of Global Left Ventricular Remodeling with the CorCap<Superscript>TM</Superscript> Cardiac Support Device Following Acute Myocardial Infarction in Sheep

Background:Whether mechanical restraint of the left ventricle (LV) can influence remodeling following myocardial infarction (MI) remains poorly understood. The following discussion details three studies examining the effects of surgically placing a cardiac support device (CSD) over the entire epicardial surface, on infarct expansion, global cardiac function and myocyte geometry and function post-MI. Methods: The effects of passive constraint on infarct expansion and global cardiac function/myocardial energetics were investigated in 10 sheep (5 MI only; 5 MI + CSD) using pressure-volume analysis and magnetic resonance imaging (MRI). Additionally, 11 sheep (5 MI only; 6 MI + CSD) were used to study the effects of passive restraint on myocyte geometry and function post-MI, with 10 additional uninstrumented sheep serving as controls. Baseline data was collected followed by the creation of an anterior infarct. 1 week post-infarct the animals underwent a second set of data collection studies followed by placement of the CSD in the experimental groups. Additional data was collected at 2 and 3 months post-MI. The animals in the myocyte function group underwent additional studies immediately following the 3 month time point. Results: Infarct expansion was diminished as a result of the CSD. At 1 week post-MI the akinetic area was similar in both groups. At the terminal time-point, the akinetic area in the control group was similar to the 1-week time-point whereas, in the CSD group, the area of akinesis decreased (P = 0.001). A comparison of the two groups at the terminal time-point demonstrates a significantly diminished area of akinesis in the CSD group (P = 0.004). The relative area of akinesis followed a similar pattern. The CSD group also exhibited a decrease in end-diastolic volume (control 110.3 ± 19.8 mL vs. CSD 67.6 ± 4.7 mL, P = .006) and an improved ejection fraction (control 15.5% ± 5.7% vs. CSD 29.46% ± 4.42%, P = .008) relative to the control group. Myocardial energetics were also enhanced in the CSD group as evidenced by significant improvements in potential energy (control 2015 ± 503 mL ⋅ mm Hg/beat vs. CSD 885 ± 220 mL ⋅ Hg/beat, P = .006), efficiency (control 39.4% ± 13.6% vs. CSD 59.8% ± 8.5%, P = .044), and oxygen consumption (control 0.072 ± 0.013 mL O₂/beat vs. CSD 0.052 ± 0.007 mL O₂/beat, P = .034). Isolated LV myocyte shortening velocity was reduced by 35% from control values (P < 0.05) in both MI groups. LV myocyte β-adrenergic response was reduced with MI, but normalized in the MI + CSD group. Relative collagen content was increased and matrix metalloproteinase-9 was decreased within the MI border region of the CSD group. Conclusions:The CorCap cardiac support device retarded infarct expansion, improved global and regional cardiac function and beneficially modified LV and myocyte remodeling post-MI. These findings provide evidence that non-pharmacological strategies can interrupt adverse LV remodeling post-MI.     

Carvedilol improves left ventricular function in murine coxsackievirus-induced acute myocarditis association with reduced myocardial interleukin-1beta and MMP-8 expression and a modulated immune response

BACKGROUND: Proinflammatory cytokines induce the expression of matrix metalloproteinases that play a crucial role in myocardial remodeling. Beta-adrenergic receptor stimulation influences the production of cytokines heralding the possibility of modulating cytokine production by beta-adrenergic blockers. METHODS AND RESULTS: In a coxsackievirus B3 murine myocarditis model (BALB/c), effects of carvedilol and metoprolol on myocardial cytokine expression, inflammatory cell infiltration and MMP/TIMP profiles were investigated. In carvedilol-treated mice, a significant improvement in left ventricular function was documented 10 days post infection. In infected mice (n=10), IL-1beta, TNF-alpha, TGF-beta(1) and IL-10 myocardial mRNA abundance were increased significantly (240%, 200%, 161%, and 230%) compared to controls (n=10), while IL-15 mRNA was markedly reduced (70%). Infected mice showed significantly increased infiltrations with CD3-, CD4- and CD8-T-lymphocytes (730%, 1110%, 380%). In the infected mice, myocardial MMP/TIMP profiles presented a significant upregulation of membrane type-1 MMP, MMP-9, MMP-8 and MMP-3 (150%, 160%, 340%, and 270%) and a significant decrease in TIMP-4 levels (75%). Carvedilol attenuated over-expression of myocardial TGF-beta(1), IL-1beta and MMP-8 mRNA expression significantly and induced a relevant IL-10 mRNA expression in the infected mice (n=10). By an unchanged infiltration with CD3-T-lymphocytes, carvedilol showed a representative reduction in CD4-T-lymphocytes. CONCLUSION: Carvedilol treatment in experimental myocarditis leads to reduced expression of proinflammatory cytokines and MMPs, which contributes to reduced matrix degradation and ultimately to improved structural integrity of the heart. Besides the antiadrenergic potential, carvedilol is beneficial due to a wide range of biological activities (antiinflammatory, antifibrotic, antioxidative and immunomodulatory).     

MMP Induction and Inhibition in Myocardial Infarction

Short-term survival following a myocardial infarction (MI) has greatly improved, due in part to therapeutic interventions that restore blood flow and limit infarct size. The increased incidence of infarct-stimulated left ventricular (LV) remodeling that advances to congestive heart failure (CHF), however, is a significant long-term complication and a leading cause of mortality. Changes to ECM structure and function are primary components of LV remodeling and are precipitated by the early increase in infarct area collagen levels that replace necrotic myocytes and form a scar. ECM turnover is coordinated through the synthesis and degradation of ECM and non-ECM components, particularly the matrix metalloproteinases (MMP), a family of proteolytic enzymes that cleave ECM. MMPs have multiple roles in remodeling events that lead to LV dilation. The inhibition or targeted deletion of specific MMPs attenuates LV remodeling events post-MI. MMP inhibitors have been used in animal models to delineate LV remodeling mechanisms and to evaluate the pharmacologic potential of targeting the ECM to modify LV remodeling post-MI. This review summarizes the current knowledge and limitations of MMP inhibition in the post-MI myocardium.     

Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling

OBJECTIVE: Interleukin-10 (IL-10) exerts potent anti-inflammatory actions and modulates matrix metalloproteinase expression. We hypothesized that endogenous IL-10 may regulate infarct healing and left ventricular remodeling by promoting resolution of the post-infarction inflammatory response and by modulating extracellular matrix metabolism. METHODS: IL-10 null and wildtype (WT) mice underwent reperfused infarction protocols. We compared the healing response and remodeling-associated parameters between IL-10-/-and WT infarcts. In addition, we studied the effects of IL-10 on inflammatory gene synthesis by stimulated murine cardiac fibroblasts. RESULTS: Infarcted IL-10-/-mice exhibited comparable mortality rates with WT animals. Although IL-10-/-mice had higher peak tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1/CCL2 mRNA levels in the infarcted heart than WT mice, both groups demonstrated timely repression of pro-inflammatory cytokine and chemokine mRNA synthesis after 24 h of reperfusion and exhibited a similar time course of resolution of the neutrophil infiltrate. IL-10 gene disruption did not alter fibrous tissue deposition and dilative remodeling of the infarcted heart. Pre-incubation with IL-10 did not modulate the pro-inflammatory phenotype of TNF-alpha-stimulated cardiac fibroblasts, failing to inhibit chemokine mRNA synthesis. In contrast, transforming growth factor (TGF)-beta1 pre-incubation suppressed interferon-gamma-inducible protein (IP)-10/CXCL10 synthesis by cardiac fibroblasts exposed to TNF-alpha. CONCLUSIONS: IL-10 signaling plays a non-critical role in suppression of inflammatory mediators, resolution of the inflammatory response, and fibrous tissue deposition following myocardial infarction. This may be due to the relative selectivity of IL-10-mediated anti-inflammatory actions, with respect to cell type and stimulus. Resolution of post-infarction inflammation is likely to involve multiple overlapping regulatory mechanisms controlling various pro-inflammatory pathways activated in the infarcted myocardium.     

Effect of granulocyte-macrophage colony-stimulating factor inducer on left ventricular remodeling after acute myocardial infarction

OBJECTIVES: We sought to determine the influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) induction on post-myocardial infarction (MI) remodeling, especially in relation to the inflammatory response and myocardial fibrosis. BACKGROUND: Granulocyte-macrophage colony-stimulating factor modifies wound healing by promoting monocytopoiesis and infiltration of monocytes and macrophages into injured tissue; however, the effect of GM-CSF induction on the infarct healing process and myocardial fibrosis is unclear. METHODS: A model of MI was produced in Wistar rats by ligation of the left coronary artery. The MI animals were randomized to receive GM-CSF inducer (romurtide 200 microg/kg/day for 7 consecutive days) (MI/Ro) or saline (MI/C). RESULTS: Echocardiographic and hemodynamic studies on day 14 revealed increased left ventricular (LV) end-diastolic dimension, decreased fractional shortening, elevated LV end-diastolic pressure, and decreased LV maximum rate of isovolumic pressure development in MI/Ro compared with MI/C. Immunoblotting showed that expression of transforming growth factor (TGF)-beta1 in the infarcted site on day 3 after MI was decreased in MI/Ro compared with MI/C. In the infarcted site, TGF-beta1, collagen type I and type III messenger ribonucleic acid (mRNA) expression on day 3, and collagen content on day 7 were reduced in MI/Ro compared with MI/C, in association with marked infarct expansion. In MI/Ro, monocyte chemoattractant protein-1 mRNA level and the degree of infiltration of monocyte-derived macrophages (ED-1-positive)were greater in the infarcted site on day 7 than those in MI/C. CONCLUSIONS: The GM-CSF induction by romurtide facilitated infarct expansion in association with the promotion of monocyte recruitment and inappropriate collagen synthesis in the infarcted region during the early phase of MI.     

Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure?

Increased activity of matrix metalloproteinases (MMPs) has been implicated in numerous disease processes, including tumor growth and metastasis, arthritis, and periodontal disease. It is now becoming increasingly clear that extracellular matrix degradation by MMPs is also involved in the pathogenesis of cardiovascular disease, including atherosclerosis, restenosis, dilated cardiomyopathy, and myocardial infarction. Administration of synthetic MMP inhibitors in experimental animal models of these cardiovascular diseases significantly inhibits the progression of, respectively, atherosclerotic lesion formation, neointima formation, left ventricular remodeling, pump dysfunction, and infarct healing. This review focuses on the role of MMPs in cardiovascular disease, in particular myocardial infarction and the subsequent progression to heart failure. MMPs, which are present in the myocardium and capable of degrading all the matrix components of the heart, are the driving force behind myocardial matrix remodeling. The recent finding that acute pharmacological inhibition of MMPs or deficiency in MMP-9 attenuates left ventricular dilatation in the infarcted mouse heart led to the proposal that MMP inhibitors could be used as a potential therapy for patients at risk for the development of heart failure after myocardial infarction. Although these promising results encourage the design of clinical trials with MMP inhibitors, there are still several unresolved issues. This review describes the biology of MMPs and discusses new insights into the role of MMPs in several cardiovascular diseases. Attention will be paid to the central role of the plasminogen system as an important activator of MMPs in the remodeling process after myocardial infarction. Finally, we speculate on the use of MMP inhibitors as potential therapy for heart failure.