ABSTRACT
OBJECTIVE: To evaluate the effects of impaired glucose tolerance (IGT) on ventricular remodeling. METHODS: Parameters of every subject including left ventricular mass (LVM), left ventricular mass index (LVMI), E/A ratio, 75 g oral glucose tolerance test (OGTT), ambulatory blood pressure monitoring (ABPM) data including 24-hour mean systolic blood pressure (mSBP) and 24-hour mean diastolic blood pressure (mDBP) were collected. Then the relationship of IGT and myocardial remodeling related parameters were analyzed. RESULTS: The rate of diastolic dysfunction was higher in the IGT combined with hypertensive group (74%) compared with the hypertensive group (39%) (χ(2) = 6.5, P < 0.05). The rate of diastolic dysfunction was higher in the IGT group (34%) compared with the normal group (10%) (χ(2) = 5.2, P < 0.05). The rate of Left Ventricular Hypertrophy (LVH) in the IGT combined with hypertensive group (24%) was higher than the other three groups (Hypertension group 7%, IGT group 0, Normal group 0) (χ(2) = 4.56 1, P < 0.05), and there was no significance between the rest three groups (P > 0.05). Stepwise multiple regression showed age and 2 Hours' Postprandial Blood Glucose were independent risk factors of E/A ratio. CONCLUSIONS: These results suggested that IGT is a possible contributor to left ventricular hypertrophy and diastolic dysfunction, and is one of the histopathology of left ventricular remodeling.
Subject(s)
Glucose Intolerance , Glucose Metabolism Disorders/metabolism , Glucose Metabolism Disorders/physiopathology , Ventricular Remodeling , Adult , Female , Glucose Tolerance Test , Humans , Hypertrophy, Left Ventricular/physiopathology , Male , Middle AgedABSTRACT
The androgen receptor (AR) is the most critical factor in prostate cancer progression. We previously demonstrated that silencing the AR using 2 unique small interfering RNAs (no. 8 and no. 31 AR siRNA) induces apoptotic cell death in AR-positive prostate cancer cells. To develop this AR siRNA technique into a therapy for prostate cancers, we generated an adeno-associated virus (AAV) vector to stably express a short hairpin-structured RNA (shRNA) against the AR gene in vivo. In addition to the no. 8 AR shRNA (ARHP8), we also screened a group of AR shRNAs with different sequences and identified a less effective AR shRNA (ARHP4) that was used as an shRNA control. An empty AAV vector (AAV-GFP) was used as a negative control. Intratumoral injection of AAV-ARHP8 viruses significantly suppressed tumor growth of xenografts derived from either androgen-responsive or castration-resistant prostate cancer cells. Most interestingly, systemic delivery of the AAV-ARHP8 but not AAV-ARHP4 or AAV-GFP viruses via tail vein injection eliminated xenografts within 10 days. Further analysis revealed that AAV-ARHP8 viruses dramatically reduced the expression of AR-regulated cellular survival genes and caused a dramatic apoptotic response. Taken together, our data strongly suggest that AAV-ARHP8 viruses induced a strong AR gene silencing in vivo and that systemic delivery of ARHP8 siRNA via an AAV vector or any other means might be considered as novel gene therapy for prostate cancers.
Subject(s)
Adenocarcinoma/therapy , Dependovirus/genetics , Gene Silencing , Genetic Vectors/therapeutic use , Prostatic Neoplasms/therapy , RNA, Small Interfering/therapeutic use , Receptors, Androgen/genetics , Adenocarcinoma/surgery , Androgen Receptor Antagonists , Animals , Apoptosis , Cell Line, Tumor/transplantation , Combined Modality Therapy , Genetic Vectors/administration & dosage , Genetic Vectors/genetics , Humans , Injections, Intralesional , Male , Mice , Mice, Nude , Orchiectomy , Prostatic Neoplasms/surgery , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Recently we reported that silencing the androgen receptor (AR) gene reduced Bcl-xL expression that was associated with a profound apoptotic cell death in prostate cancer cells. In this study we further investigated AR-regulated Bcl-xL expression. METHODS: Prostate cancer cell line LNCaP and its sublines, LNCaP/PURO and LNCaP/Bclxl, were used for cell proliferation assay and xenograft experiments in nude mice. Luciferase gene reporters driven by mouse or human bcl-x gene promoter were used to determine androgen regulation of Bcl-xL expression. RT-PCR and Western blot assays were conducted to assess Bcl-xL gene expression. Chromatin immunoprecipitation assay was performed to determine AR interaction with Bcl-xL promoter. Bcl-xL-induced alteration of gene expression was examined using cDNA microarray assay. RESULTS: In cultured prostate cancer LNCaP cells, androgen treatment significantly increased Bcl-xL expression at mRNA and protein levels via an AR-dependent mechanism. Promoter analyses demonstrated that the AR mediated androgen-stimulated bcl-x promoter activation and that the AR interacted with bcl-x promoter. Enforced expression of Bcl-xL gene dramatically increased cell proliferation in vitro and promoted xenograft tumor growth in vivo. Genome-wide gene profiling analysis revealed that Bcl-xL expression was significantly higher in metastatic and castration-resistant diseases compared to normal prostate tissues or primary cancers. Bcl-xL overexpression significantly increased the expression of cyclin D2, which might be responsible for Bcl-xL-induced cell proliferation and tumor growth. CONCLUSIONS: Taken together, our data strongly suggest that androgen stimulates Bcl-xL expression via the AR and that increased Bcl-xL expression plays a versatile role in castration-resistant progression of prostate cancer.
