RESUMEN
AIMS: Controversial results have been provided regarding the potential role of proteasome subunit alpha type 6 gene (PSMA6) in determining susceptibility to myocardial infarction (MI). In addition, no data in Caucasians have been provided. We aimed to: (a) validate in a Caucasian population the association between PSMA6 gene polymorphism and MI; (b) investigate the potential association between PSMA6 gene variants and MI in type 2 diabetics; (c) evaluate a potential functional role of PSMA6 allelic variants. METHODS: 224 subjects (73 patients with MI and 151 controls) were genotypized for variants of PSMA6 gene. In 36 patients, biopsy specimens were taken from the left ventricle area of presumed ischemia for ubiquitin-proteasome activity quantification. RESULTS: Allele frequency and genotype distribution of all PSMA6 gene polymorphisms studied did not differ between patients with MI and controls. When the analysis was restricted to type 2 diabetics (n=119), a different rs_1048990 C/G allele frequency and genotype distribution was found having diabetic subjects with MI (n=34) higher G allele frequency compared to controls (n=85), (p=0.02). Myocardial ubiquitin levels (r=0.75; p<0.001) and proteasome 20S (r=0.7; p<0.01) activity significantly correlated with plasma glucose even after adjusting for covariates. Type 2 diabetic subjects had higher myocardial ubiquitin levels (p<0.001) and proteasome 20S activity (p<0.001) compared to non-diabetics. Subjects carriers the allele G at rs_1048990 loci had higher myocardial ubiquitin levels and proteasome 20S activity. CONCLUSION: PSMA6 rs_1048990 polymorphism may contribute to MI susceptibility in type 2 diabetes. Up-regulation of ubiquitin-proteasome pathway may be a potential mechanism for explaining such association.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Infarto del Miocardio/genética , Polimorfismo Genético/genética , Complejo de la Endopetidasa Proteasomal/genética , Población Blanca/genética , Anciano , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/etnología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Italia , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etnología , Infarto del Miocardio/patología , Ubiquitina/fisiologíaRESUMEN
Whether morning blood pressure surge influences the molecular mechanisms of plaque progression toward instability is not known. Recently, we have demonstrated enhanced activity of the ubiquitin-proteasome system in human plaques and evidenced that it is associated with inflammatory-induced plaque rupture. We evaluated the inflammatory infiltration and ubiquitin-proteasome activity in asymptomatic carotid plaques of hypertensive patients with different patterns of morning blood pressure surge. Plaques were obtained from 32 hypertensive patients without morning blood pressure surge and 28 with morning blood pressure surge enlisted to undergo carotid endarterectomy for extracranial high-grade (>70%) internal carotid artery stenosis. Plaques were analyzed for macrophages, T-lymphocytes, human leukocyte antigen-DR+cells, ubiquitin-proteasome activity, nuclear factor-kappaB, inhibitor kB-beta, tumor necrosis factor-alpha, nitrotyrosine, matrix metalloproteinase-9, and collagen content (immunohistochemistry and ELISA). Compared with plaques obtained from hypertensive patients without morning blood pressure surge, plaques from with morning blood pressure surge had more macrophages, T-lymphocytes, human leukocyte antigen-DR+cells (P<0.001), ubiquitin-proteasome activity, tumor necrosis factor-alpha, nuclear factor-kB (P<0.001), nitrotyrosine, and matrix metalloproteinase-9 (P<0.01), along with a lesser collagen content and IkB-beta levels (P<0.001). Enhanced ubiquitin-proteasome activity in atherosclerotic lesions of patients with morning blood pressure surge is associated with inflammatory-dependent unstable plaque phenotype. These data suggest a potential interplay between morning blood pressure surge and ubiquitin-proteasome activity in atherosclerosis pathophysiology.
Asunto(s)
Presión Sanguínea , Enfermedades de las Arterias Carótidas/patología , Ritmo Circadiano , Hipertensión/fisiopatología , Arteriosclerosis Intracraneal/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Monitoreo Ambulatorio de la Presión Arterial , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/metabolismo , Humanos , Hipertensión/complicaciones , Técnicas In Vitro , Inflamación/metabolismo , Inflamación/patología , Arteriosclerosis Intracraneal/complicaciones , Arteriosclerosis Intracraneal/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Tirosina/análogos & derivados , Tirosina/metabolismo , Regulación hacia ArribaRESUMEN
OBJECTIVE: Stress hyperglycemia has been associated with increased mortality in patients with myocardial infarction (MI). We examined the association between plasma glucose levels, circulating inflammatory markers, T-cell activation, and functional cardiac outcome in patients with first MI. RESEARCH DESIGN AND METHODS: Echocardiographic parameters, circulating levels of interleukin-18 (IL-18), C-reactive protein (CPR), and the percent of CD16-CD56, CD4/CD8, CD152, and HLA-DR expression were investigated in 108 patients with acute MI on admission to the emergency ward. RESULTS: Our review found that 31 new hyperglycemic patients (glycemia >or=7 mmol/l) had higher infarct segment length (P < 0.05) and myocardial performance index (P < 0.02) and reduced transmitral Doppler flow (P < 0.05), pulmonary flow analysis (P < 0.02), and ejection fraction (P < 0.05) compared with 36 hyperglycemic diabetic patients and 41 normoglycemic patients. Plasma IL-18 and CRP were higher in the hyperglycemic than in the normoglycemic patients (P < 0.005), with the highest values in patients with new hyperglycemia (P < 0.05). Hyperglycemic patients had a higher percent of CD16+/CD56+ cells and CD4/CD8 ratio (P < 0.01), whereas they had lower CD152 expression (which has a negative regulatory function in T-cell activation) compared with normoglycemic patients (P < 0.001). CONCLUSIONS: During MI, hyperglycemia is associated with increased levels of inflammatory markers, enhanced expression of cytotoxic T-cells, and reduced expression of T-cells, which are implicated in limiting the immune process. An increased inflammatory immune process seems a likely mechanism linking acute hyperglycemia to poor cardiac outcome in MI patients.