The membrane type-1 matrix metalloproteinase (MT1-MMP) is a unique member of the MMP family, but induction patterns and consequences of MT1-MMP overexpression (MT1-MMPexp), in a left ventricular (LV) remodeling process such as myocardial infarction (MI), have not been explored. MT1-MMP promoter activity (murine luciferase reporter) increased 20-fold at 3 days and 50-fold at 14 days post-MI. MI was then induced in mice with cardiac restricted MT1-MMPexp (n = 58) and wild type (WT, n = 60). Post-MI survival was reduced (67% versus 46%, p < 0.05), and LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT (41 ± 2 versus 32 ± 2%,p < 0.05). In the post-MI MT1-MMPexp mice, LV myocardial MMP activity, as assessed by radiotracer uptake, and MT1-MMP-specific proteolytic activity using a specific fluorogenic assay were both increased by 2-fold. LV collagen content was increased by nearly 2-fold in the post-MI MT1-MMPexp compared with WT. Using a validated fluorogenic construct, it was discovered that MT1-MMP proteolytically processed the pro-fibrotic molecule, latency-associated transforming growth factor-1 binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by 4-fold in the post-MI MT1-MMPexp group. Early and persistent MT1-MMP promoter activity occurred post-MI, and increased myocardial MT1-MMP levels resulted in poor survival, worsening of LV function, and significant fibrosis. A molecular mechanism for the adverse LV matrix remodeling with MT1-MMP induction is increased processing of pro-fibrotic signaling molecules. Thus, a proteolytically diverse portfolio exists for MT1-MMP within the myocardium and likely plays a mechanistic role in adverse LV remodeling. 相似文献
In order to investigate the pharmacological basis of ‘Yang-invigorating’ action, the effect of oral treatment with the methanolic extract of ‘Yang-invigorating’ herbs on ATP-generation capacity was examined, using heart homogenates prepared from herb-pretreated mice. Tonifying (i.e., health-promoting) herbs of other functional categories were also included for comparison. The results indicated that ‘Yang-invigorating’ Chinese tonifying herbs could invariably enhance myocardial ATP-generation capacity, with the extent of stimulation varying among the herbs. In contrast, ‘Yin-nourishing’ herbs either did not stimulate or even decreased myocardial ATP-generation capacity. While ‘Qi-invigorating’ herbs produced variable effects on myocardial ATP-generation capacity, most of the ‘blood-enriching’ herbs did not cause any significant changes. The results obtained from studies using myocardial mitochondrial fractions isolated from herb-pretreated mice suggest that ‘Yang-invigorating’ herbs might speed up ATP generation by increasing mitochondrial electron transport. The ensemble of results has provided evidence for the first time to support the pharmacological basis of ‘Yang invigoration’ in Chinese medicine. 相似文献
The abilities of chemically generated hydroxyl radical (OH), superoxide anion (O?) and hydrogen peroxide (H2O2) to degrade rat myocardial membrane phospholipids previously lableed with [1 -14C]arachidonic acid were studied. HO and H2O2 but not O2??, caused the degradation of phospha-tidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI). With OH' and H2O2, the loss of radiolable in PC was accompanied by an increase in the radiolabel of lysophosphatidylcholine (LPC), but not in that of free fatty acid (FFA). These results suggest the hydrolysis of l-oxygen ester bond of PC by HO' and that H2O2 and that HO' and H2O2, but not O?, are detrimental to the structure and function of membrane phospholipids. However, since μM amounts of HO' and mM amounts of H2O2 were necessary to affect the membrane phospholipids, it is likely that in the reprefused myocardium only HO', but not H2O2, may directly cause the breakdown of membrane phospholipids. 相似文献
Summary The substructure of the inner mitochondrial membranes has been studied by cryo-ultramicrotomy under conditions during which denaturation of proteins by treatment with chemical solutes has been totally avoided. In such preparations, the inner membrane has a substructure consisting of globular subunits. These subunits have an average diameter of ca. 20Å–ca. 62Å and are fairly regularly spaced. Intracristal space is absent in the unstained, freeze-dried preparations, whereas a space of ca 40Å is seen in preparations lightly treated by OsO4-vapour. It is concluded that the subunits of the inner mitochondrial membranes probably consist either of single protein molecules or of complexes of protein molecules.This work was supported by grants from The Norwegian Council on Cardiovascular Disease and from The Norwegian Research Council for Science and the Humanities 相似文献
The mechanical state of the heart feeds back to modify cardiac rate and rhythm. Mechanical stretch of myocardial tissue causes immediate and chronic responses that lead to the common end point of arrhythmia. This review provides a brief summary of the author's personal choice of contributions that she considers have fostered our understanding of the role of mechano-electric feedback in arrhythmogenesis.
Acute mechanical stretch reversibly depolarises the cell membrane and shortens the action potential duration. These electrophysiological changes are related to the activation of mechano-sensitive ion channels. Several different ion channels are involved in the sensing of stretch, among them K+-selective, Cl−-selective, non-selective, and ATP-sensitive K+ channels. Sodium and Ca2+ entering the cells via non-selective ion channels are thought to contribute to the genesis of stretch-induced arrhythmia. Mechano-sensitive channels have been cloned from non-vertebrate and vertebrate species.
Chronic stress on the heart activates gene expression in cardiomyocytes and non-myocytes. The signal transduction involves atrial natriuretic peptides and growth factors that initiate remodelling processes leading to hypertrophy which in turn may contribute to the electrical instability of the heart by increasing the responsiveness of mechano-sensitive channels. Selective block of these channels could provide some new form of treatment of mechanically induced arrhythmias, although at present there are no drugs available with sufficient selectivity. Detailed understanding of how mechanical strain on myocardial cells is translated into channel activation will allow to identify new targets for putative antiarrhythmic drugs. 相似文献