扶正化瘀胶囊对心肌梗死大鼠心肌纤维化的影响

目的：急性心肌梗死是危害人类健康的重大疾病之一,心肌梗死后心肌纤维化是造成心脏结构破坏、心功能下降、心律失常发生、心衰甚至猝死的微观病理机制。防治心肌纤维化是当前医学研究的重点和热点。本研究主要探讨扶正化瘀胶囊对心肌梗死大鼠心肌纤维化的干预作用。方法：大鼠随机分为假手术组、模型组、扶正化瘀胶囊组和卡托普利组,采用结扎冠状动脉前降支的方法建立心肌梗死模型,假手术组只穿线,不结扎。于造模成功后第10天开始给予相应药物治疗2个月。治疗结束后,检测左心室梗死范围和心肌胶原含量。结果：与假手术组比较,模型组、扶正化瘀胶囊组和卡托普利组的非梗死区面积显著减小（P〈0.01）。与模型组比较,扶正化瘀胶囊组和卡托普利组的梗死区面积和梗死百分比显著减小（P〈0.05,P〈0.01）。在心肌胶原表达上,与假手术组比较,模型组和扶正化瘀胶囊组胶原含量显著增加（P〈0.01）。与模型组比较,卡托普利组和扶正化瘀胶囊组胶原含量显著降低（P〈0.05,P〈0.01）。结论：扶正化瘀胶囊能够改善心肌缺血,缩小心肌梗死范围,抑制心肌胶原表达,除能用于肝纤维化的治疗外,还能用于防治心肌梗死后的心肌纤维化。     

Histological differences in healing following experimental transmural infarction in rats

Mechanisms of cardiac regeneration following transmural myocardial infarction were analysed in rat hearts using immunohistochemistry for a-SMA, caspase-3, Ki-67 and nestin markers. Seven weeks after experimental myocardial infarction, two different types of healing processes were revealed in rats with and without aneurysmatic bulging of the left ventricular wall. Besides thinning of the ventricular wall, three zones characterized both types of scars: the scar zone (divided into central and peripheral parts), the peri-infarct zone and the border zone. The main difference between the types of scars was the presence of a central necrotic zone inside the aneurysmatic wall, while connective tissue with myofibroblasts characterized the same zone in non-bulging wall. Apoptotic caspase-3 positive cells were found in the granulation tissue of the border zone in aneurysmatic scar, while in non-bulging scar they characterized all three zones. Proliferating Ki-67 positive cells displayed reverse expression pattern compared to apoptotic cells. Quantification of a-SMA positive cells revealed 60% a-SMA positive cells inside the central part of the aneurysmatic scar zone and 39% in invaginating areas, versus 19% in non-invaginating areas of the peripheral zone, but only 30% in the peripheral part of the non-bulging scar zone. Nestin positive cells were found in both types of scars, but with different distribution. These results suggest that even seven weeks after myocardial infarction, the healing processes in non-bulging scars are in chronic phase, while aneurysmatic scars are still in subacute phase. Histological differences in scar healing might be important for functional properties of the heart wall and for heart recovery prognosis.     

A role for decorin in the remodeling of myocardial infarction.

Because the small leucine-rich proteoglycan decorin has been implicated in regulation of collagen fibrillogenesis leading to proper extracellular matrix assembly, we hypothesized it could play a key role in cardiac fibrosis following myocardial infarction. In this study we ligated the left anterior descending coronary artery in wildtype and decorin-null mice to produce large infarcts in the anterior wall of the left ventricle. At early stages post-coronary occlusion the myocardial infarction size did not appreciably differ between the two genotypes. However, we found a wider distribution of collagen fibril sizes with less organization and loose packing in mature scar from decorin-null mice. Thus, we tested the hypothesis that these abnormal collagen fibrils would adversely affect post-infarction mechanics and ventricular remodeling. Indeed, scar size, right ventricular remote hypertrophy, and left ventricular dilatation were greater in decorin-null animals compared with wildtype littermates 14 days after acute myocardial infarction. Echocardiography revealed depressed left ventricular systolic function between 4 and 8 weeks post-ischemia in the decorin-null animals. These changes indicate that decorin is required for the proper fibrotic evolution of myocardial infarctions, and that its absence leads to abnormal scar tissue formation. This might contribute to aneurysmal ventricular dilatation, remote hypertrophy, and depressed ventricular function.     

Interaction between left ventricular wall motion and intraventricular flow propagation in acute and chronic ischemia

Myocardial ischemia has been associated with left ventricular (LV) postsystolic shortening. The combination of tissue Doppler imaging and high frame-rate acquisition of two-dimensional color flow makes it possible to study the interaction between LV wall motion and intraventricular flow propagation. The aim of this study was to examine in a clinical model the impact that acute myocardial ischemia and prior myocardial infarct might have on LV flow patterns and to explain the underlying mechanisms from the tissue Doppler data. LV flow propagation and tissue velocities during early diastole were studied in 18 healthy individuals, 17 patients with prior anterior myocardial infarct, and 16 patients before and during percutaneous coronary intervention (PCI) of the left anterior descending artery. Normal individuals had intraventricular flow propagation toward the apex during isovolumic relaxation. During this early diastolic time phase, myocardial velocities measured at mid- and apical septal segment were directed away from the apex. Before PCI, patients without myocardial infarction had similar findings as in normal individuals. In contrast, each patient with either prior myocardial infarction or PCI-induced acute ischemia had flow propagation opposite to normal individuals, and tissue velocities reversed toward the apex during early diastole. Reversal of early diastolic LV flow propagation in acute and chronic anterior myocardial ischemia reflects postsystolic shortening in the dyskinetic apical and septal myocardial segments.     

Alteration of collagenous protein profile in congestive heart failure secondary to myocardial infarction

The rat model of myocardial infarction is characterized by progressive cardiac hypertrophy and failure. Rats with infarcts greater than 30% of the left ventricle exhibited early and moderate, stages of heart failure 4 and 8 weeks after the occlusion of the left coronary artery, respectively. As heart failure is usually associated with remodeling of the extracellular matrix, a histological and biochemical study of cardiac collagenous proteins was carried out using failing hearts. Total collagen content in the right ventricle increased at 2, 4, and 8 weeks following occlusion of the left coronary artery whereas such a change in viable left ventricle was seen after 4 and 8 weeks. Total cardiac hydroxyproline concentration was increased in both right and left ventricular samples from the infarcted animals when compared to those of control; this increase was due to elevation of pepsin-insoluble collagen fraction. The myocardial noncollagenous/collagenous protein ratio was decreased in experimental right and left ventricular samples when compared to control samples. These findings suggest that an increase in cross-linking of cardiac collagen as well as disparate synthesis of collagenous and noncollagenous proteins occurs in this model of congestive heart, failure.     

Depression Increases Sympathetic Activity and Exacerbates Myocardial Remodeling after Myocardial Infarction: Evidence from an Animal Experiment

Depression is an independent risk factor for cardiovascular events and mortality in patients with myocardial infarction (MI). Excessive sympathetic activation and serious myocardial remodeling may contribute to this association. The aim of this study was to discuss the effect of depression on sympathetic activity and myocardial remodeling after MI. Wild-type (WT) rats were divided into a sham group (Sham), a myocardial infarction group (MI), a depression group (D), and a myocardial infarction plus depression group (MI+D). Compared with controls, the MI+D animals displayed depression-like behaviors and attenuated body weight gain. The evaluation of sympathetic activity showed an increased level in plasma concentrations of epinephrine and norepinephrine and higher expression of myocardial tyrosine hydroxylase in the MI+D group than the control groups (p<0.05 for all). Cardiac function and morphologic analyses revealed a decreased fractional shortening accompanied by increased left ventricular dimensions, thinning myocardium wall, and reduced collagen repair in the MI+D group compared with the MI group (p<0.05 for all). Frequent premature ventricular contractions, prolonged QT duration and ventricular repolarization duration, shorted effective refractory period, and increased susceptibility to ventricular arrhythmia were displayed in MI+D rats. These results indicate that sympathetic hyperactivation and exacerbated myocardial remodeling may be a plausible mechanism linking depression to an adverse prognosis after MI.     

心肌细胞／胶原复合体移植心梗大鼠梗死周边区的电偶联网络变化

目的应用免疫组化技术和电生理技术记录心肌细胞／胶原复合体对心梗大鼠梗死周边区的有效不应期（ERP）及缝隙连接蛋白43（Cx43）改变,探讨梗死周边区的电偶联网络变化。方法将成年SD大鼠随机分组：假手术组、模型组、移植组。后2组制作心肌梗死动物模型,假手术组仅开胸,不结扎冠状动脉,移植组移植心肌细胞与胶原材料复合组织。结果①左室ERP变化：与假手术组相比,心梗组梗死周边区ERP显著延长（P〈0．01）;移植组梗死周边区ERP延长,但较心梗阻ERP缩短,差异无显著性（P〉0．01）。②Cx43免疫组化结果：移植组Cx43阳性蛋白表达高于心梗组。结论移植的心肌细胞／胶原复合体移植可改善大鼠心肌梗死周边区缝隙连接电偶联网络,进而调控心肌细胞／胶原复合体与宿主心肌同步收缩。     

Apoptosis at a distance: remote activation of caspase-3 occurs early after myocardial infarction

Objective: After an acute myocardial infarction, the viable myocardium remote from the infarct zone is subjected to ventricular remodeling. Besides hypertrophy, processes of apoptosis may contribute to these remodeling processes. Reports on apoptosis in this area have been doubted because they were mainly based on in-situ nick-end DNA labeling (TUNEL) measurements, with questionable specifity. Moreover, the time course of initiation of these processes has not been characterized. Therefore the goals of this study were to (1) reliably determine if in the remote area of the infarcted heart apoptosis may be initiated using highly specific biochemical markers and (2) evaluate the time course of such an activation. Methods: A well-defined model, regional myocardial infarction induced by ligation of the left anterior coronary artery in rats in vivo, was used. Heart and lung wet weights, the left ventricular end-diastolic pressure (LVEDP), and the serum level of the atrial natriuretic propeptide (proANP) were determined from 1 day up to 4 weeks as indicators of developing heart failure. In transmural biopsies from the non-ischemic left ventricular wall of the infarcted heart, the activation of caspase-3, the bcl-2/bax ratio (Western blot analysis), and the DNA laddering (LM-PCR) were determined. Results: Although heart- and lung weights did not increase before 1 week after infarction, proANP levels were elevated already 1 day after myocardial infarction suggesting early sub-clinical heart failure. The activity of caspase-3 increased significantly to 160± 20% compared to sham operated controls as early as 1 day after ligation and remained elevated over the entire time course. In parallel, the bcl-2/bax ratio shifted toward the pro-apoptotic bax. Moreover, these clear and specific biochemical indicators of apoptosis in the remote area of the infarcted heart were paralleled by the fragmentation of genomic DNA. Conclusion: These data demonstrate that apoptotic markers are activated in the surviving zone of the heart remote from the infarct area as early as 1 day after myocardial infarction with persistence for up to 4 weeks. This activation coincides with early markers of heart failure. The exact regulation of this apoptotic process remains to be elucidated. Parts of this study were presented at the Annual Meetings of the American College of Cardiology 2002.     

Systematic Characterization of Myocardial Inflammation,Repair, and Remodeling in a Mouse Model of Reperfused Myocardial Infarction

Mouse models of myocardial infarction are essential tools for the study of cardiac injury, repair, and remodeling. Our current investigation establishes a systematic approach for quantitative evaluation of the inflammatory and reparative response, cardiac function, and geometry in a mouse model of reperfused myocardial infarction. Reperfused mouse infarcts exhibited marked induction of inflammatory cytokines that peaked after 6 hr of reperfusion. In the infarcted heart, scar contraction and chamber dilation continued for at least 28 days after reperfusion; infarct maturation was associated with marked thinning of the scar, accompanied by volume loss and rapid clearance of cellular elements. Echocardiographic measurements of end-diastolic dimensions correlated well with morphometric assessment of dilative remodeling in perfusion-fixed hearts. Hemodynamic monitoring was used to quantitatively assess systolic and diastolic function; the severity of diastolic dysfunction following myocardial infarction correlated with cardiomyocyte hypertrophy and infarct collagen content. Expression of molecular mediators of inflammation and cellular infiltration needs to be investigated during the first 72 hr, whereas assessment of dilative remodeling requires measurement of geometric parameters for at least four weeks after the acute event. Rapid initiation and resolution of the inflammatory response, accelerated scar maturation, and extensive infarct volume loss are important characteristics of infarct healing in mice.     

Multi-modality imaging evaluation of recurrent Tako-tsubo syndrome in a patient with coronary artery fibromuscular dysplasia

Background

Integrated bedside and sophisticated cardiac imaging techniques help characterize the discrepancy between myocardial injury and mechanic dysfunction in acute myocardial infarction.

Case presentation

A 57 year-old woman presented with sudden onset chest pain and ventricular fibrillation after hearing of her brother’s death. The electrocardiography indicated “anterior wall ST segment elevation myocardial infarction”. Coronary angiography ruled out obstructive lesion in the major coronary arteries, but revealed fibromuscular dysplasia of the distal left anterior descending artery. The ventriculography showed remarkable ventricular dilation, which affected much broader myocardium than the culprit vessel supplied. In a subsequent cardiac magnetic resonance study, delayed contrast (gadolinium) image revealed a focal left ventricular (LV) apical infarction. Her LV systolic function normalized within 1 week, except for a residual apical hypokinesis. She developed recurrent chest pain and LV dilation when she was laid off 9 months later. After supportive therapy, her symptoms improved and LV dysfunction normalized again.

Conclusions

“Tako-tsubo” syndrome can occur recurrently in the heart with pre-existing localized myocardial infarction. Its molecular mechanism and clinical significance warrants further investigation.

     

Proteinases and myocardial extracellular matrix turnover

Extracellular structural remodeling is the compensatory response of the tissue following pathological stage. Myocardial infarction, which leads to adverse remodeling, thinning of the ventricle wall, dilatation and heart failure, is one of the leading causes of death. Remodeling implies an alteration in the extracellular matrix and in the spatial orientation of cells and intracellular components. The extracellular matrix is responsible for cardiac cell alignment and myocardial structural integrity. Substances that break down the extracellular matrix, specialized proteinases as well as inhibitors of proteinases, appear to be normally balanced in maintaining the integrity of the myocardium. Myocardial infarction leads to an imbalance in proteinase/ antiproteinase activities causing alterations in the stability and integrity of the extracellular matrix and adverse tissue remodeling. To explore mechanisms involved in this process and, in particular, to focus on matrix metalloproteinases, their inhibitors, and activators, an understanding of proteinase and antiproteinase is needed. This review represents new and significant information regarding the role of activated matrix proteinases antiproteinases in remodeling. Such information will have a significant impact both on the understanding of the basic cell biology of extracellular matrix turnover, as well as on potential avenues for pharmacological approaches to the treatment of ischemic heart disease and failure.     

Isolated Aortocoronary Bypass Operations in Patients Over 70 Years of Age: A Comparison With Results in Patients 50 to 59 Years Old

The early and late morbidity, mortality and beneficial effects of isolated aortocoronary bypass operations in a group of 35 patients 70 years old or older were compared with those factors in patients 50 to 59 years old. The patients in both groups were matched according to the year in which the operation was done and the number of vessels bypassed. Left ventricular function, estimated by the angiographically calculated ejection fraction, was not statistically different in the two groups. Cardiac index, while adequate in both groups, was significantly lower in the older age group. Comparisons were made of “early” events, such as perioperative myocardial infarction, perioperative death and length of post-operative hospital stay; and of “late” events, including myocardial infarction, angina pectoris, congestive heart failure and death, which occurred after patients were discharged from the hospital. The mean length of follow-up of patients was similar in both groups.In comparing early events in the two groups, there was no statistically significant difference in the incidence of perioperative myocardial infarction, perioperative mortality or mean length of postoperative hospital stays. With regard to late events, there was no statistically significant difference in the incidences of myocardial infarction, angina pectoris or mortality.     

Congestive heart failure. New frontiers.

Congestive heart failure is a common syndrome with high mortality in its advanced stages. Current therapy includes the use of vasodilator drugs, which have been shown to prolong life. Despite current therapy, mortality remains high in patients with severe heart failure. Potent new inotropic vasodilators have improved ventricular performance but have not prolonged life in patients with end-stage heart failure. Serious arrhythmias are implicated in the sudden deaths of 30% to 40% of patients with severe heart failure, but the benefits of antiarrhythmic therapy have not been established. Upcoming trials will address this question. Ventricular remodeling and progressive dilatation after myocardial infarction commonly lead to congestive heart failure; early unloading of the ventricle with an angiotensin-converting enzyme inhibitor may attenuate these events. These findings support the concept that angiotensin-converting enzyme inhibitors may be useful in managing heart failure of all degrees of severity, including left ventricular dysfunction and end-stage heart failure. Part of the damage that may occur with acute myocardial infarction, particularly in this era of thrombolysis therapy, is reperfusion injury, which may be mediated by oxygen-derived free radicals. Better knowledge of the mechanisms and treatment of myocardial infarction, the leading cause of congestive heart failure, may help prevent or attenuate the development of this syndrome.     

FGF-16 is required for embryonic heart development

Fibroblast growth factor 16 (FGF-16) expression has previously been detected in mouse heart at mid-gestation in the endocardium and epicardium, suggesting a role in embryonic heart development. More specifically, exogenously applied FGF-16 has been shown to stimulate growth of embryonic myocardial cells in tissue explants. We have generated mice lacking FGF-16 by targeting the Fgf16 locus on the X chromosome. Elimination of Fgf16 expression resulted in embryonic death as early as day 11.5 (E11.5). External abnormalities, including hemorrhage in the heart and ventral body region as well as facial defects, began to appear in null embryos from E11.5. Morphological analysis of FGF-16 null hearts revealed cardiac defects including chamber dilation, thinning of the atrial and ventricular walls, and poor trabeculation, which were visible at E10.5 and more pronounced at E11.5. These findings indicate FGF-16 is required for embryonic heart development in mid-gestation through its positive effect on myocardial growth.     

Therapeutic drugs during healing after myocardial infarction modify infarct collagens and ventricular distensibility at elevated pressures

We investigated whether therapeutic drugs given during healing following acute myocardial infarction (AMI) modify infarct collagens and left ventricular (LV) distensibility. We treated dogs with drugs from major classes (i.e., indomethacin, ibuprofen, captopril, enalapril, verapamil, amlodipine, propranolol, isosorbide dinitrate [ISDN] and digoxin) between day 2 and 6 weeks and measured hemodynamics, LV remodeling and function during healing over 6 weeks after transmural anterior AMI, and regional collagens, LV distensibility under increasing pressure, rupture threshold (RT), and topography at 6 weeks. Relative to sham, AMI controls showed infarct zone (IZ) expansion and thinning, 9.3-fold increase in IZ collagen, LV dilation and dysfunction, and no change in distensibility and RT. Relative to controls, indomethacin as well as enalapril, captopril and amlodipine decreased IZ collagen. Infarct expansion was attenuated by ibuprofen, captopril, amlodipine and ISDN but augmented by indomethacin. Infarct thinning was prevented by captopril, amlodipine and ISDN but enhanced by indomethacin. Importantly, indomethacin and enalapril enhanced LV distensibility and lowered RT. Distensibility correlated positively with IZ type III collagen and negatively with type I/III collagen ratio and pyridinoline cross-links whereas RT correlated positively with IZ type I collagen. Systolic volume and ejection fraction deteriorated with indomethacin but were improved or preserved with other therapies. The results demonstrate that different therapeutic drugs may produce different effects on IZ collagens during healing post-AMI: drugs that attenuate or adversely alter IZ collagens also enhance LV distensibility, augment adverse remodeling and lower RT, suggesting that testing for these effects post-AMI is warranted.     

Autologous stem cell transplantation for myocardial repair

Current therapies for heart failure due to transmural left ventricular (LV) infarction are limited. We have developed a novel patch method for delivering autologous bone marrow stem cells to sites of myocardial infarction for the purpose of improving LV function and preventing LV aneurysm formation. The patch consisted of a fibrin matrix seeded with autologous porcine mesenchymal stem cells labeled with lacZ. We applied this patch to a swine model of postinfarction LV remodeling. Myocardial infarction was produced by using a 60-min occlusion of the left anterior descending coronary artery distal to the first diagonal branch followed by reperfusion. Results were compared between eight pigs with stem cell patch transplantation, six pigs with the patch but no stem cells (P), and six pigs with left anterior descending coronary artery ligation alone (L). Magnetic resonance imaging data collected 19 +/- 1 days after the myocardial infarction indicated a significant increase of LV systolic wall thickening fraction in the infarct zone of transplanted hearts compared with P or L hearts. Blue X-gal staining was observed in the infarcted area of transplanted hearts. PCR amplification of specimens from the X-gal-positive area revealed the Ad5 RSV-lacZ vector fragment DNA sequence. Light microscopy demonstrated that transplanted cells had differentiated into cells with myocyte-like characteristics and a robust increase of neovascularization as evidenced by von Willebrand factor-positive angioblasts and capillaries in transplanted hearts. Thus this patch-based autologous stem cell procedure may serve as a therapeutic modality for myocardial repair.     

Protective effect of lycopene on cardiac function and myocardial fibrosis after acute myocardial infarction in rats via the modulation of p38 and MMP-9

Extracellular matrix (ECM) plays an important role in maintaining the left ventricular geometry and ventricular function, and the inhibition of ECM remodeling has therapeutic benefits that could alleviate the progression of ventricular remodeling. Recent studies have indicated that lycopene has cardioprotective effects. In this study, a rat myocardial infarction (MI) model was established by left anterior descending coronary artery ligation. After the operation, the rats received lycopene or saline. After 28 days, the rats underwent echocardiography detection and were sacrificed. Myocardial fibrosis was observed by Masson staining. Type I collagen, MMP-9, and MAPK protein expression were detected in the ischemic zone surrounding the MI by western blot. Treatment with lycopene increased the EF from 45.2 ± 3.12 % to 51.1 ± 4.63, and it decreased the LVEDd from 6.52 ± 0.37 mm to 6.18 ± 0.41 mm and the LVESd from 4.29 ± 0.63 to 3.94 ± 0.37 at 28 days post-myocardial infarction. Lycopene attenuated the MI-induced increase in MMP-9 and type I collagen expression, and inhibited p38 activation. Moreover, lycopene decreased the collagen volume fraction in the peri-infarcted zone. The data indicated that lycopene improved the cardiac function and ventricular remodeling by inhibiting p38 activation and MMP-9 expression.     

Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish

The zebrafish heart has the capacity to regenerate after ventricular resection. Although this regeneration model has proved useful for the elucidation of certain regeneration mechanisms, it is based on the removal of heart tissue rather than its damage. Here, we characterize the cellular response and regenerative capacity of the zebrafish heart after cryoinjury, an alternative procedure that more closely models the pathophysiological process undergone by the human heart after myocardial infarction (MI). Localized damage was induced in 25% of the ventricle by cryocauterization (CC). During the first 24 hours post-injury, CC leads to cardiomyocyte death within the injured area and the near coronary vasculature. Cell death is followed by a rapid proliferative response in endocardium, epicardium and myocardium. During the first 3 weeks post-injury cell debris was cleared and the injured area replaced by a massive scar. The fibrotic tissue was subsequently degraded and replaced by cardiac tissue. Although animals survived CC, their hearts showed nonhomogeneous ventricular contraction and had a thickened ventricular wall, suggesting that regeneration is associated with processes resembling mammalian ventricular remodeling after acute MI. Our results provide the first evidence that, like mammalian hearts, teleost hearts undergo massive fibrosis after cardiac damage. Unlike mammals, however, the fish heart can progressively eliminate the scar and regenerate the lost myocardium, indicating that scar formation is compatible with myocardial regeneration and the existence of endogenous mechanisms of scar regression. This finding suggests that CC-induced damage in zebrafish could provide a valuable model for the study of the mechanisms of scar removal post-MI.     

Dynamic induction of ADAMTS1 gene in the early phase of acute myocardial infarction

Extracellular matrix (ECM)-degrading enzymes such as matrix metalloproteases (MMPs) play an essential role in the repair of infarcted tissue, which affects ventricular remodeling after myocardial infarction. ADAMTS1 (A disintegrin and metalloprotease with thrombospondin motifs), a newly discovered metalloprotease, was originally cloned from a cancer cell line, but little is known about its contribution to disease. To test the hypothesis that ADAMTS1 appears in infarcted myocardial tissue, we examined ADAMTS1 mRNA expression in a rat myocardial infarction model by Northern blotting, real-time RT-PCR and in situ hybridization. Normal endothelium expressed little ADAMTS1 mRNA, while normal myocardium expressed no detectable ADAMTS1 mRNA. Up-regulation of ADAMTS1 was demonstrated by Northern blot analysis and real-time RT-PCR at 3 h after coronary artery ligation. In situ hybridization revealed strong ADAMTS1 mRNA signals in the endothelium and myocardium in the infarcted heart, mainly in the infarct zone, at 3 h after myocardial infarction. The rapid and transient up-regulation of the ADAMTS1 gene in the ischemic heart was distinct from the regulatory patterns of other MMPs. Our study demonstrated that the ADAMTS1 gene is a new early immediate gene expressed in the ischemic endothelium and myocardium.     

Adenovirus-mediated stromal cell-derived factor-1 alpha gene transfer improves cardiac structure and function after experimental myocardial infarction through angiogenic and antifibrotic actions

Stromal cell-derived factor 1α (SDF-1) is not only a major chemotactic factor, but also an inducer of angiogenesis. The effects of SDF-1α on the left ventricular remodeling in a rat myocardial infarction (MI) model were analyzed. Myocardial infarction was induced by ligation of the left coronary artery in rats. 0.5 × 10¹⁰ pfu/ml AdV-SDF-1 or 0.5 × 10¹⁰ pfu/ml Adv-LacZ were immediately injected into the infarcted myocardium, 120 μl cell-free PBS were injected into the infarcted region or the myocardial wall in control, and sham group, respectively. We found that AdV-SDF-1 group had higher LVSP and ±dP/dt_max, lower LVEDP compared to control or Adv-LacZ group. The number of c-Kit⁺ stem cells, and gene expression of SDF-1, VEGF and bFGF were obviously increased, which was associated with reduced infarct size, thicker left ventricle wall, greater vascular density and cardiocytes density in infarcted hearts of AdV-SDF-1 group. Furthermore, the expression of collagen type I and type III mRNA, and collagen accumulation in the infarcted area was lower, which was associated with decreased TGF-β1, TIMP-1 and TIMP-2 expression in AdV-SDF-1 group. Conclusion: SDF-1α could improve cardiac structure and function after Myocardial infarction through angiogenic and anti-fibrotic actions.