Angiographic no-reflow phenomenon strongly predicts long-term cardiac complications after AMI; these complications are possibly associated with LV remodeling.

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Background— Mineralocorticoid receptor antagonism reduces mortality associated with heart failure by mechanisms that remain unclear. The effects of the mineralocorticoid receptor antagonist spironolactone on left ventricular (LV) function and chamber stiffness associated with myocardial fibrosis were investigated in mildly symptomatic patients with idiopathic dilated cardiomyopathy (DCM). Methods and Results— Twenty-five DCM patients with a New York Heart Association functional class of I or II were examined before and after treatment with spironolactone for 12 months. LV pressures and volumes were measured simultaneously, and LV endomyocardial biopsy specimens were obtained. Serum concentrations of the carboxyl-terminal propeptide (PIP) and carboxyl-terminal telopeptide (CITP) of collagen type I were measured. The patients were divided into 2 groups on the basis of the serum PIP/CITP ratio (≤35, group A, n=12; >35, group B, n=13), an index of myocardial collagen accumulation. LV diastolic chamber stiffness, the collagen volume fraction, and abundance of collagen type I and III mRNAs in biopsy tissue were greater and the LV early diastolic strain rate (tissue Doppler echocardiography) was smaller in group B than in group A at baseline. These differences and the difference in PIP/CITP were greatly reduced after treatment of patients in group B with spironolactone, with treatment having no effect on these parameters in group A. The collagen volume fraction was significantly correlated with PIP/CITP, LV early diastolic strain rate, and LV diastolic chamber stiffness for all patients before and after treatment with spironolactone. Conclusions— Spironolactone ameliorated LV diastolic dysfunction and reduced chamber stiffness in association with regression of myocardial fibrosis in mildly symptomatic patients with DCM. These effects appeared limited, however, to patients with increased myocardial collagen accumulation.

Abstract-Matrix metalloproteinases (MMPs) have been implicated in the process of neovascularization. However, the exact roles of individual MMPs in vessel formation are poorly understood. To study the putative role of MMP-2 in ischemia-induced neovascularization, a hindlimb ischemia model was applied to MMP-2 ϩ/ϩ and MMP-2 Ϫ/Ϫ mice. Serial laser Doppler blood-flow analysis revealed that the recovery of the ischemic/normal blood-flow ratio in MMP-2 Ϫ/Ϫ young and old mice remained impaired throughout the follow-up period. At day 35, microangiography and anti-L-lectin immunohistochemical staining revealed lesser developed collateral vessels and capillary formation in both old and young MMP-2 Ϫ/Ϫ mice compared with the age-matched MMP-2 ϩ/ϩ mice. An aortic-ring culture assay showed a markedly impaired angiogenic response in MMP-2 Ϫ/Ϫ mice, which was partially recovered by supplementation of the culture medium with recombinant MMP-2. Aorta-derived endothelial cells or bone marrow-derived endothelial progenitor cell (EPC)-like c-Kit ϩ cells from MMP-2 Ϫ/Ϫ showed marked impairment of invasive or/and proliferative abilities. At day 7, plasma and ischemic tissues of vascular endothelial growth factor protein were reduced in MMP-2 Ϫ/Ϫ . Flow cytometry showed that the numbers of EPC-like CD31 ϩ c-Kit ϩ cells in peripheral blood markedly decreased in MMP-2-deficient mice. Transplantation of bone marrow-derived mononuclear cells from MMP-2 ϩ/ϩ mice restored neovascularization in MMP-2 Ϫ/Ϫ young mice. These data suggest that MMP-2 deficiency impairs ischemia-induced neovascularization through a reduction of endothelial cell and EPC invasive and/or proliferative activities and EPC mobilization. (Circ Res. 2007;100:904-913.) Key Words: ischemia Ⅲ angiogenesis Ⅲ matrix metalloproteinase Ⅲ endothelium Ⅲ mobilization Ⅲ migration I t is well known that the process of new blood vessel formation is associated with extracellular matrix (ECM) remodeling involving various proteolytic systems. Among such systems, matrix metalloproteinases (MMPs) are a family of zincdependent endopeptidases comprising at least 20 members that are collectively capable of degrading all known ECM components. 1,2 A number of studies have shown that various kinds of MMPs were upregulated in ischemia-induced angiogenesis. 3 Although MMP activity is commonly thought to be involved in the process of angiogenesis, this notion has been challenged by recent studies using genetic or biological target methods. It has been reported that MMP-9 deficiency reduced neovascularization and tumor growth. 4 Study of membrane-type1 (MT1)-MMP knockout mice revealed that the deficiency impaired neovascularization in a mouse corneal micropocket model. 5 Whereas MMP-1 and MMP-10 appear to control the process of vascular regression rather than morphogenesis. 6 On the other hand, certain MMPs, including MMP-12 and MMP-7, are capable of converting plasminogen into angiostatin to inhibit endothelial cell (EC) tubulogenesis in vitro. 7 Interestingly, it has been reported that tiss...

The present experiment was performed to identify endothelium-derived contracting factor produced by acetylcholine stimulation in the aorta of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The rings of the thoracic aorta were obtained from age-matched SHR and WKY rats, and changes in isometric tension were recorded. The relaxant responses to acetylcholine in the aortic rings from SHR were significantly weaker than those from WKY rats. The relaxant responses to acetylcholine were significantly enhanced by pretreatment with a cyclooxygenase inhibitor (indomethacin) or thromboxane A 2 / prostaglandin H 2 receptor antagonist (ONO-3708) in aortic rings from both SHR and WKY rats. A thromboxane A 2 synthetase inhibitor (OKY-046) did not affect the acetylcholineinduced relaxation in the aortic rings from SHR or WKY rats. In the organ bath solution, after acetylcholine stimulation, prostaglandin E 2 and 6-keto-prostaglandin F la concentrations increased but not prostaglandin F 2a and thromboxane B 2 concentrations. Exogenous prostaglandin H 2 , a stable analogue of thromboxane A 2 , and prostaglandin F 2a induced contractions of the SHR rings at a lower concentration than prostaglandin E 2 , prostaglandin D 2 , and prostaglandin I 2 . These contractile responses to various prostaglandins were markedly inhibited by pretreatment with ONO-3708. A prostacyclin synthetase inhibitor did not affect the relaxant responses to acetylcholine in the SHR rings. These results show that endotheliumderived contracting factor is produced and released by acetylcholine stimulation not only in the aorta of SHR but also in those of WKY rats and suggest that prostaglandin H 2 , a precursor of the released prostaglandins, is a strong candidate for endothelium-derived contracting factor produced by acetylcholine stimulation. (Hypertension 1990;15:475-481) A ll blood vessels are lined by the endothelium, and the important role of an organic or functional abnormality of endothelial cells in the pathogenesis and pathophysiology of various diseases has attracted attention.In 1980, Furchgott et al 1 found that acetylcholine induced endothelium-dependent relaxation in the rabbit aorta. Since then, various substances have been reported to induce endothelium-dependent relaxation in most of the blood vessels in mammals. 23Several pharmacological observations have strongly suggested that there is more than one endothelium-

Abstract-Atherosclerosis-based vascular disease is an inflammatory disease characterized by extensive remodeling of the extracellular matrix architecture of the arterial wall. Although matrix metalloproteinases and serine proteases participate in these pathological events, the discovery of cysteine protease cathepsins, such as cathepsins K, S, L, and B, and cystatin C, and their tissue distribution has suggested that at least some of them participate in cardiovascular disease. Studies on vascular cells have shown that atherosclerosis-associated inflammatory cytokines augment cysteinyl cathepsin expression and activity. Novel insight into cathepsin functions has been made possible by the generation and in-depth analysis of knockout and transgenic mice. These studies have provided direct evidence implicating cathepsins in atherosclerosis-based vascular disease through the activation, liberation, and modification of angiogenic growth factors, cytokines, and proteases associated with lipid metabolism, cell events (migration, invasion, proliferation, and apoptosis), angiogenesis, and matrix protein remodeling. Furthermore, evaluation of the feasibility of cathepsins as a diagnostic tool has revealed that the serum cathepsins S and L and the endogenous inhibitor cystatin C hold promise as biomarkers of coronary artery disease and aneurysm formation.

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Background Exercise stimulates the vascular response in pathological conditions, including ischemia; however, the molecular mechanisms by which exercise improves the impaired hypoxia-induced factor (HIF)-1α–mediated response to hypoxia associated with aging are poorly understood. Here, we report that swimming training (ST) modulates the vascular response to ischemia in aged (24-month-old) mice. Methods and Results Aged wild-type mice (MMP-2+/+) that maintained ST (swimming 1 h/d) from day 1 after surgery were randomly assigned to 4 groups that were treated with either vehicle, LY294002, or deferoxamine for 14 days. Mice that were maintained in a sedentary condition served as controls. ST increased blood flow, capillary density, and levels of p-Akt, HIF-1α, vascular endothelial growth factor, Fit-1, and matrix metalloproteinase-2 (MMP-2) in MMP-2+/+ mice. ST also increased the numbers of circulating endothelial progenitor cells and their function associated with activation of HIF-1α. All of these effects were diminished by LY294002, an inhibitor of phosphatidylinositol 3-kinase; enhanced by deferoxamine, an HIF-1α stabilizer; and impaired by knockout of MMP-2. Finally, bone marrow transplantation confirmed that ST enhanced endothelial progenitor cell homing to ischemic sites in aged mice. Conclusions ST can improve neovascularization in response to hypoxia via a phosphatidylinositol 3-kinase–dependent mechanism that is mediated by the HIF-1α/vascular endothelial growth factor/MMP-2 pathway in advanced age.