RESUMO
Age-regulated genes may serve as markers of aging, enabling assessment of physiological aging independent of chronological age. One gene with transcripts that increase in abundance with age in human organs, inter alia in epithelial skin cells, is the chemokine growth-regulated protein alpha (GRO-alpha). When chemokines, such as GRO-alpha, become disregulated so that they are chronically expressed, tissue damage, angiogenesis, and tumorigenesis can follow. To consider the role of GRO-alpha as a potential marker for aging and cancer, we compared the transient knockdown of GRO-alpha by RNA interference in the human sebaceous gland cell line SZ95, which behaves like normal human sebocytes, and in the melanoma cell line A375, which originates from a primary human tumor. The reduced GRO-alpha RNA expression, of about 75% in SZ95 sebocytes and 58% in A375 melanoma cells, has functional consequences in normal aged cells and in cancer cells. Silencing of the proangiogenic chemokine GRO-alpha is proportionally correlated with interleukin-6 (IL-6), IL-8 and vascular endothelial growth factor secretion in both cell types. Thus, GRO-alpha may be a novel diagnostic marker for age-related pathology, including cancer.
Assuntos
Envelhecimento/metabolismo , Biomarcadores Tumorais/metabolismo , Quimiocina CXCL1/metabolismo , Melanoma/metabolismo , Neovascularização Patológica/metabolismo , Glândulas Sebáceas/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Linhagem Celular Transformada , Linhagem Celular Tumoral , Senescência Celular/genética , Quimiocina CXCL1/antagonistas & inibidores , Quimiocina CXCL1/genética , Citocinas/genética , Citocinas/metabolismo , Humanos , Melanoma/genética , Melanoma/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Interferência de RNA , RNA Interferente Pequeno/genética , Glândulas Sebáceas/patologiaRESUMO
KCNQ channels have been identified in arterial smooth muscle. However, their role in vasoregulation and chronic vascular diseases remains elusive. We tested the hypothesis that KCNQ channels contribute to periadventitial vasoregulation in peripheral skeletal muscle arteries by perivascular adipose tissue and that they represent novel targets to rescue periadventitial vascular dysfunction. Two models, spontaneously hypertensive rats and New Zealand obese mice, were studied using quantitative polymerase chain reaction, the patch-clamp technique, membrane potential measurements, myography of isolated vessels, and blood pressure telemetry. In rat Gracilis muscle arteries, anticontractile effects of perivascular fat were inhibited by the KCNQ channel blockers XE991 and linopirdine but not by other selective K(+) channel inhibitors. Accordingly, XE991 and linopirdine blocked noninactivating K(+) currents in freshly isolated Gracilis artery smooth muscle cells. mRNAs of several KCNQ channel subtypes were detected in those arteries, with KCNQ4 channels being dominant. In spontaneously hypertensive rats, the anticontractile effect of perivascular fat in Gracilis muscle arteries was largely reduced compared with Wistar rats. However, the vasodilator effects of KCNQ channel openers and mRNA expression of KCNQ channels were normal. Furthermore, KCNQ channel openers restored the diminished anticontractile effects of perivascular fat in spontaneously hypertensive rats. Moreover, KCNQ channel openers reduced arterial blood pressure in both models of hypertension independent of ganglionic blockade. Thus, our data suggest that KCNQ channels play a pivotal role in periadventitial vasoregulation of peripheral skeletal muscle arteries, and KCNQ channel opening may be an effective mechanism to improve impaired periadventitial vasoregulation and associated hypertension.