Subject(s)
Gallstones/complications , Hyperparathyroidism, Primary/complications , Aged , Cholecystectomy , Comorbidity , Female , Gallstones/epidemiology , Gallstones/surgery , Humans , Hypercalcemia/etiology , Hyperparathyroidism, Primary/epidemiology , Japan/epidemiology , Male , Matched-Pair Analysis , Middle Aged , Propensity Score , Retrospective StudiesABSTRACT
OBJECTIVE: Enhanced expression of PAI-1 (plasminogen activator inhibitor-1) has been implicated in atherosclerosis formation in humans with obesity and metabolic syndrome. However, little is known about the effects of pharmacological targeting of PAI-1 on atherogenesis. This study examined the effects of pharmacological PAI-1 inhibition on atherosclerosis formation in a murine model of obesity and metabolic syndrome. Approach and Results: LDL receptor-deficient (ldlr-/-) mice were fed a Western diet high in cholesterol, fat, and sucrose to induce obesity, metabolic dysfunction, and atherosclerosis. Western diet triggered significant upregulation of PAI-1 expression compared with normal diet controls. Addition of a pharmacological PAI-1 inhibitor (either PAI-039 or MDI-2268) to Western diet significantly inhibited obesity and atherosclerosis formation for up to 24 weeks without attenuating food consumption. Pharmacological PAI-1 inhibition significantly decreased macrophage accumulation and cell senescence in atherosclerotic plaques. Recombinant PAI-1 stimulated smooth muscle cell senescence, whereas a PAI-1 mutant defective in LRP1 (LDL receptor-related protein 1) binding did not. The prosenescent effect of PAI-1 was blocked by PAI-039 and R2629, a specific anti-LRP1 antibody. PAI-039 significantly decreased visceral adipose tissue inflammation, hyperglycemia, and hepatic triglyceride content without altering plasma lipid profiles. CONCLUSIONS: Pharmacological targeting of PAI-1 inhibits atherosclerosis in mice with obesity and metabolic syndrome, while inhibiting macrophage accumulation and cell senescence in atherosclerotic plaques, as well as obesity-associated metabolic dysfunction. PAI-1 induces senescence of smooth muscle cells in an LRP1-dependent manner. These results help to define the role of PAI-1 in atherosclerosis formation and suggest a new plasma-lipid-independent strategy for inhibiting atherogenesis.
Subject(s)
Atherosclerosis/prevention & control , Metabolic Syndrome/drug therapy , Plasminogen Activator Inhibitor 1/drug effects , Animals , Cellular Senescence/drug effects , Diet, Western , Disease Models, Animal , Indoleacetic Acids/administration & dosage , Macrophages/drug effects , Macrophages/pathology , Metabolic Syndrome/pathology , Metabolic Syndrome/prevention & control , Mice , Mice, Knockout , Obesity/etiology , Obesity/prevention & control , Plaque, Atherosclerotic/pathology , Plasminogen Activator Inhibitor 1/physiology , Receptors, LDL/deficiency , Receptors, LDL/geneticsABSTRACT
We assessed the change of homocysteine (Hcy), insulin-like growth factor one (IGF-Ι) and oestrogen (E2) levels in patients with erectile dysfunction (ED) associated with chronic hepatitis C virus (HCV) infection. Eighty-five male patients with chronic HCV and/or ED were enrolled in this study. Seventy-five men were assigned to three equal groups (n = 25/each); Group A: patients who had chronic HCV and ED. Group B: patients who had chronic HCV and had no ED complaint. Group C: patients who had ED with no chronic HCV. In addition to 10 control patients with no ED or chronic HCV (Group D). All patients were subjected to: detailed medical and sexual history, complete physical examination, laboratory assessment including measurement of serum Hcy, IGF-1 and E2. The means of international index of erectile function scores were 8 and 16 in groups A and C respectively. There were significant differences in Hcy, IGF-I and E2 among study groups (p < 0.05 for each). There were significant differences in Hcy between patients with Child B and Child C. A strong association between severity of ED and chronic HCV was demonstrated. There was statistically significant increase of Hcy and E2 levels and reduction in IGF-I level in patients with ED associated with chronic HCV infection.
