Induction of human inhibitor of apoptosis protein-2 by shear stress in endothelial cells

AbstractTo disclose the anti-atherosclerotic mechanisms of steady laminar shear stress, we analyzed the expression of human inhibitor of apoptosis protein-2 (HIAP-2), whose gene was selected from a cDNA library of sheared endothelial cells (ECs), on ECs. HIAP-2 was dose-independently and time-dependently induced in ECs by shear stress, regulated at the transcriptional level. HIAP-2 expression was also identified in vivo. Shear stress-mediated inhibition of EC apoptosis was associated with the inhibition of caspase-3 activity, suggesting that the shear stress prevents EC apoptosis via negative regulation of caspase-3 by the increment of HIAP-2

Effects of a high-fat diet on the electrical properties of porcine atria

AbstractBackgroundBecause obesity is an important risk factor for atrial fibrillation (AF), we conducted an animal study to examine the effect of a high-fat diet (HFD) on atrial properties and AF inducibility.MethodsTen 8-week-old pigs (weight, 18–23kg) were divided into two groups. For 18 weeks, five pigs were fed a HFD (HFD group) and five were fed a normal diet (control group). Maps of atrial activation and voltages during sinus rhythm were created for all pigs using the EnSite NavX system. Effective refractory period (ERP) and AF inducibility were also determined. When AF was induced, complex fractionated atrial electrogram (CFAE) mapping was performed. At 18 weeks, hearts were removed for comparing the results of histological analysis between the two groups. Body weight, lipid levels, hemodynamics, cardiac structures, and electrophysiological properties were also compared.ResultsTotal cholesterol levels were significantly higher (347 [191–434] vs. 81 [67–88]mg/dL, P=0.0088), and left atrium pressure was higher (34.5 [25.6–39.5] vs. 24.5 [21.3–27.8]mmHg, P=0.0833) in the HFD group than in the control group, although body weight only increased marginally (89 [78–101] vs. 70 [66–91]kg, P=0.3472). ERPs of the pulmonary vein (PV) were shorter (P<0.05) and AF lasted longer in the HFD group than in the control group (80 [45–1350] vs. 22 [3–30]s, P=0.0212). Neither CFAE site distribution nor histopathological characteristics differed between the two groups.ConclusionsThe shorter ERPs for the PV observed in response to the HFD increased vulnerability to AF, and these electrophysiological characteristics may underlie obesity-related AF

Activation of EDTA-resistant gelatinases in malignant human tumors

Among the many proteases associated with human cancer, seprase or fibroblast activation protein alpha, a type II transmembrane glycoprotein, has two types of EDTA-resistant protease activities: dipeptidyl peptidase and a 170-kDa gelatinase activity. To test if activation of gelatinases associated with seprase could be involved in malignant tumors, we used a mammalian expression system to generate a soluble recombinant seprase (r-seprase). In the presence of putative EDTA-sensitive activators, r-seprase was converted into 70- to 50-kDa shortened forms of seprase (s-seprase), which exhibited a 7-fold increase in gelatinase activity, whereas levels of dipeptidyl peptidase activity remained unchanged. In malignant human tumors, seprase is expressed predominantly in tumor cells as shown by in situ hybridization and immunohistochemistry. Proteins purified from experimental xenografts and malignant tumors using antibody- or lectin-affinity columns in the presence of 5 mmol/L EDTA were assayed for seprase activation in vivo. Seprase expression and activation occur most prevalently in ovarian carcinoma but were also detected in four other malignant tumor types, including adenocarcinoma of the colon and stomach, invasive ductal carcinoma of the breast, and malignant melanoma. Together, these data show that, in malignant tumors, seprase is proteolytically activated to confer its substrate specificity in collagen proteolysis and tumor invasion

Stabilization of atherosclerotic plaque by pitavastatin in Watanabe heritable hyperlipidemic rabbits: A serial tissue-characterizing intravascular ultrasound study

AbstractBackgroundTo examine the effects of pitavastatin on atherosclerotic plaque in Watanabe heritable hyperlipidemic (WHHL) rabbits using serial in vivo tissue-characterizing intravascular ultrasound.MethodsA total of 11 WHHL rabbits of 10–12 weeks of age were divided into two groups, control and pitavastatin-administered groups. A total of 29 atherosclerotic plaque segments from control group and 43 plaque segments from the pitavastatin group were serially imaged by 40MHz intravascular ultrasound in vivo with a tissue characterization software (iMAP™, Boston Scientific, Natick, MA, USA) at the baseline and the follow-up (16th week).ResultsThe level of low-density lipoprotein cholesterol was significantly decreased in pitavastatin group. During the follow-up period, plaque area was significantly increased in the control group, whereas it was not significantly changed in the pitavastatin group. The fibrotic, necrotic, and necrotic plus lipidic areas were significantly increased in the control group, while no significant change was revealed for tissue profile in pitavastatin group. The change in the percent areas of fibrotic and lipidic plus necrotic tissues were significantly different between the two groups especially in the superficial half portion of plaque.ConclusionsThese data indicate that pitavastatin could attenuate atherosclerotic plaque formation and that it could stabilize the plaque in WHHL rabbits. Considering the fact that these were observed even with a high follow-up level of cholesterol, these data might come from the pleiotropic effects of pitavastatin