Background -Neutrophils and monocytes are centrally linked to vascular inflammatory disease, and leukocyte-derived myeloperoxidase(MPO) has emerged as an important mechanistic participant in impaired vasomotor functio...Background -Neutrophils and monocytes are centrally linked to vascular inflammatory disease, and leukocyte-derived myeloperoxidase(MPO) has emerged as an important mechanistic participant in impaired vasomotor function. MPO binds to and transcytoses endothelial cells in a glycosaminoglycan-dependent manner, and MPO binding to the vessel wall is a prerequisite for MPO-dependent oxidation of endothelium-derived nitric oxide(NO) and impairment of endothelial function in animal models. In the present study, we investigated whether heparin mobilizes MPO from vascular compartments in humans and defined whether this translates into increased vascular NO bioavailability and function. Methods and Results -Plasma MPO levels before and after heparin administration were assessed by ELISA in 109 patients undergoing coronary angiography. Whereas baseline plasma MPO levels did not differ between patients with or without angiographically detectable coronary artery disease(CAD), the increase in MPO plasma content on bolus heparin administration was higher in patients with CAD(P=0.01). Heparin treatment also improved endothelial NO bioavailability, as evidenced by flow-mediated dilation(P< 0.01) and by acetylcholine-induced changes in forearm blood flow(P< 0.01). The extent of heparin-induced MPO release was correlated with improvement in endothelial function(r=0.69, P< 0.01). Moreover, and consistent with this tenet, ex vivo heparin treatment of extracellular matrix proteins, cultured endothelial cells, and saphenous vein graft specimens from CAD patients decreased MPO burden. Conclusions -Mobilization of vessel-associated MPO may represent an important mechanism by which heparins exert antiinflammatory effects and increase vascular NO bioavailability. These data add to the growing body of evidence for a causal role of MPO in compromised vascular NO signaling in humans.展开更多
This study assessed apparently normal mitral valves from patients with congestive heart failure(CHF)using biochemical and echocardiographic measures of extracellular matrix(ECM)and anatomy. Mitral regurgitation(MR)is ...This study assessed apparently normal mitral valves from patients with congestive heart failure(CHF)using biochemical and echocardiographic measures of extracellular matrix(ECM)and anatomy. Mitral regurgitation(MR)is frequently found in patients with CHF. This MR is considered purely functional, yet animal studies suggest that altered left ventricular(LV)function leads to increased cellularity and fibrosis of the mitral valve. Therefore, we hypothesized that patients with CHF might have partly organic MR, via dysfunctional valvular remodeling. Mitral valves from transplant recipient hearts of patients with CHF(23 dilated, 14 ischemic)were analyzed for deoxyribonucleic acid(DNA), collagen, glycosaminoglycan(GAG), and water concentrations and compared with autopsy controls. Cardiac dimensions and functional parameters(measured from recent echocardiograms)were compared with biochemical parameters using a repeated measures generalized linear model. The mitral valves in CHF had up to 78%more DNA(p < 0.03), 59%more GAGs(p < 0.02), and 15%more collagen(p < 0.007), but 7%less water(p < 0.05)than normal. The absence of anterior leaflet redundancy was associated with these deranged biochemical measures(p< 0.03). Associations were found between leaflet thickness and DNA concentration(+, p=0.003), annular diameter and chordal collagen(+, p=0.03), and water concentration and both left atrial diameter(-, p=0.008)and LV collagen concentration(-, p=0.04). Mitral valves in CHF are biochemically different from normal, with ECM changes that are influenced by the altered cardiac dimensions. This remodeling suggests that MR in patients with CHF may not be purely functional, and that these valves are not “normal.”展开更多
Objective. The extracellular glycosaminoglycan hyaluronan (HA) and its degradative enzymes, hyaluronidases (Hyal), play important roles in tumor metastasis and angiogenesis. HA promotes tumor cell adhesion and migrati...Objective. The extracellular glycosaminoglycan hyaluronan (HA) and its degradative enzymes, hyaluronidases (Hyal), play important roles in tumor metastasis and angiogenesis. HA promotes tumor cell adhesion and migration, while its cleaved fragments stimulate angiogenesis. The aims of this study were to assess the levels of HA and how it might be regulated in endometrial cancer. Methods. Endometrial carcinomas were grouped according to histologic grade (Grade 1- 3). HA histochemistry utilized a biotinylated HA binding peptide (n = 15), while HA synthase (HAS) immunohistochemistry utilized an antibody recognizing HAS1, HAS2 HAS3 (n = 24). Real-time RT-PCR was used to determine the mRNA expression of Hyal 1, Hyal 2 (n = 13) and Hyal 3 (n = 11) in endometrial carcinomas. Results. HA, its synthases and degradative enzymes were identified in endometrial carcinomas of all histologic grades. HA was predominantly localized to tumor-associated stroma. Semiquantitative analysis revealed increased HA levels with tumor grade, however, this increase only attained significance in Grade 2 carcinomas (P < 0.05). HA staining intensity scores were significantly associated with the presence of myometrial invasion (P < 0.05). Alternatively, HAS was predominantly localized in tumor epithelial cells, and its levels did not vary with tumor grade. Expression of Hyal 3 and Hyal 2 mRNA were >1000- fold and >30- fold greater respectively than that of Hyal 1 mRNA, the major Hyal expressed in other cancers. No Hyal type varied with tumor grade. Conclusion. This is the first study to demonstrate the cellular localization of HA and its synthases and that Hyal 3 mRNA is predominant in endometrial cancer. The results suggest a role for elevated HA in endometrial cancer progression.展开更多
文摘Background -Neutrophils and monocytes are centrally linked to vascular inflammatory disease, and leukocyte-derived myeloperoxidase(MPO) has emerged as an important mechanistic participant in impaired vasomotor function. MPO binds to and transcytoses endothelial cells in a glycosaminoglycan-dependent manner, and MPO binding to the vessel wall is a prerequisite for MPO-dependent oxidation of endothelium-derived nitric oxide(NO) and impairment of endothelial function in animal models. In the present study, we investigated whether heparin mobilizes MPO from vascular compartments in humans and defined whether this translates into increased vascular NO bioavailability and function. Methods and Results -Plasma MPO levels before and after heparin administration were assessed by ELISA in 109 patients undergoing coronary angiography. Whereas baseline plasma MPO levels did not differ between patients with or without angiographically detectable coronary artery disease(CAD), the increase in MPO plasma content on bolus heparin administration was higher in patients with CAD(P=0.01). Heparin treatment also improved endothelial NO bioavailability, as evidenced by flow-mediated dilation(P< 0.01) and by acetylcholine-induced changes in forearm blood flow(P< 0.01). The extent of heparin-induced MPO release was correlated with improvement in endothelial function(r=0.69, P< 0.01). Moreover, and consistent with this tenet, ex vivo heparin treatment of extracellular matrix proteins, cultured endothelial cells, and saphenous vein graft specimens from CAD patients decreased MPO burden. Conclusions -Mobilization of vessel-associated MPO may represent an important mechanism by which heparins exert antiinflammatory effects and increase vascular NO bioavailability. These data add to the growing body of evidence for a causal role of MPO in compromised vascular NO signaling in humans.
文摘This study assessed apparently normal mitral valves from patients with congestive heart failure(CHF)using biochemical and echocardiographic measures of extracellular matrix(ECM)and anatomy. Mitral regurgitation(MR)is frequently found in patients with CHF. This MR is considered purely functional, yet animal studies suggest that altered left ventricular(LV)function leads to increased cellularity and fibrosis of the mitral valve. Therefore, we hypothesized that patients with CHF might have partly organic MR, via dysfunctional valvular remodeling. Mitral valves from transplant recipient hearts of patients with CHF(23 dilated, 14 ischemic)were analyzed for deoxyribonucleic acid(DNA), collagen, glycosaminoglycan(GAG), and water concentrations and compared with autopsy controls. Cardiac dimensions and functional parameters(measured from recent echocardiograms)were compared with biochemical parameters using a repeated measures generalized linear model. The mitral valves in CHF had up to 78%more DNA(p < 0.03), 59%more GAGs(p < 0.02), and 15%more collagen(p < 0.007), but 7%less water(p < 0.05)than normal. The absence of anterior leaflet redundancy was associated with these deranged biochemical measures(p< 0.03). Associations were found between leaflet thickness and DNA concentration(+, p=0.003), annular diameter and chordal collagen(+, p=0.03), and water concentration and both left atrial diameter(-, p=0.008)and LV collagen concentration(-, p=0.04). Mitral valves in CHF are biochemically different from normal, with ECM changes that are influenced by the altered cardiac dimensions. This remodeling suggests that MR in patients with CHF may not be purely functional, and that these valves are not “normal.”
文摘Objective. The extracellular glycosaminoglycan hyaluronan (HA) and its degradative enzymes, hyaluronidases (Hyal), play important roles in tumor metastasis and angiogenesis. HA promotes tumor cell adhesion and migration, while its cleaved fragments stimulate angiogenesis. The aims of this study were to assess the levels of HA and how it might be regulated in endometrial cancer. Methods. Endometrial carcinomas were grouped according to histologic grade (Grade 1- 3). HA histochemistry utilized a biotinylated HA binding peptide (n = 15), while HA synthase (HAS) immunohistochemistry utilized an antibody recognizing HAS1, HAS2 HAS3 (n = 24). Real-time RT-PCR was used to determine the mRNA expression of Hyal 1, Hyal 2 (n = 13) and Hyal 3 (n = 11) in endometrial carcinomas. Results. HA, its synthases and degradative enzymes were identified in endometrial carcinomas of all histologic grades. HA was predominantly localized to tumor-associated stroma. Semiquantitative analysis revealed increased HA levels with tumor grade, however, this increase only attained significance in Grade 2 carcinomas (P < 0.05). HA staining intensity scores were significantly associated with the presence of myometrial invasion (P < 0.05). Alternatively, HAS was predominantly localized in tumor epithelial cells, and its levels did not vary with tumor grade. Expression of Hyal 3 and Hyal 2 mRNA were >1000- fold and >30- fold greater respectively than that of Hyal 1 mRNA, the major Hyal expressed in other cancers. No Hyal type varied with tumor grade. Conclusion. This is the first study to demonstrate the cellular localization of HA and its synthases and that Hyal 3 mRNA is predominant in endometrial cancer. The results suggest a role for elevated HA in endometrial cancer progression.
