Background Persons with pre-diabetes and diabetes are at high risk for cardiovascular events. However, the relationships of pre-diabetes and diabetes to development of subclinical myocardial damage are unclear. Methods and Results We measured cardiac troponin T with a highly sensitive assay (hs-cTnT) at two time points, 6 years apart, among 9,331 participants of the community-based Atherosclerosis Risk in Communities (ARIC) Study with no diabetes, pre-diabetes, or diabetes but without cardiovascular disease including silent MI by ECG. First, we examined incidence of elevated hs-cTnT (≥14 ng/L) at 6 years of follow-up. Second, we examined clinical outcomes during the subsequent ~14 years of follow-up among persons with and without incident elevated hs-cTnT. Cumulative probabilities of elevated hs-cTnT at 6 years among persons with no diabetes, pre-diabetes, and diabetes were 3.7%, 6.4%, and 10.8%, respectively. Compared to normoglycemic persons, the adjusted relative risks for incident elevated hs-cTnT were 1.38 (95%CI 1.07-1.77) for pre-diabetes and 2.46 (95%CI 1.77-3.42) for diabetes. Persons with diabetes and incident elevations in hs-cTnT were at a substantially higher risk of heart failure (HR 6.37, 95%CI 4.27-9.51), death (HR 4.36, 95%CI 3.14-6.07) and coronary heart disease (HR 3.84, 95%CI 2.52-5.84) compared to persons without diabetes and no incident elevation in hscTnT. Conclusions Pre-diabetes and diabetes were independently associated with development of subclinical myocardial damage, as assessed by hs-cTnT, and those persons with evidence of subclinical damage were at highest risk for clinical events. These results support a possible deleterious effect of hyperglycemia on the myocardium, possibly reflecting a microvascular etiology.
Bile salt export pump (BSEP) is responsible for biliary secretion of bile acids, a rate limiting step in the enterohepatic circulation of bile acids and transactivated by nuclear receptor farnesoid x receptor (FXR). Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent disorder among diseases unique to pregnancy and primarily occurs in the third trimester of pregnancy with a hallmark of elevated serum bile acids. Currently, the transcriptional regulation of BSEP during pregnancy and its underlying mechanisms and involvement in ICP are not fully understood. In this study, the dynamics of BSEP transcription in vivo in the same group of pregnant mice before, during and after gestation were established with in vivo imaging system (IVIS). BSEP transcription was markedly repressed in the later stages of pregnancy and immediately recovered after parturition, resembling the clinical course of ICP in human. The transcriptional dynamics of BSEP was inversely correlated with serum 17β-estradiol (E2) levels before, during and after gestation. Further studies showed that E2 repressed BSEP expression in human primary hepatocytes, Huh 7 cells and in vivo in mice. Such transrepression of BSEP by E2 in vitro and in vivo required estrogen receptor α (ERα). Mechanistic studies with chromatin immunoprecipitation (ChIP), protein co-immunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC) assays demonstrated that ERα directly interacted with FXR in living cells and in vivo in mice. In conclusion, BSEP expression was repressed by E2 in the late stages of pregnancy through a non-classical E2/ERα transrepressive pathway, directly interacting with FXR. E2-mediated repression of BSEP expression represents an etiological contributing factor to ICP and therapies targeting the ERα/FXR interaction may be developed for prevention and treatment of ICP.
An emerging body of data suggests that the early onset of Alzheimer’s disease (AD) is associated with decreased brain-derived neurotrophic factor (BDNF). Because BDNF plays a critical role in the regulation of high-frequency synaptic transmission and long-term potentiation in the hippocampus, the up-regulation of BDNF may rescue cognitive impairments and learning deficits in AD. In the present study, we investigated the effects of hippocampal BDNF in a rat model of AD produced by a ventricle injection of amyloid-β1-42 (Aβ1-42). We found that a ventricle injection of Aβ1-42 caused learning deficits in rats subjected to the Morris water maze and decreased BDNF expression in the hippocampus. Chronic intra-hippocampal BDNF administration rescued learning deficits in the water maze, whereas infusions of NGF and NT-3 did not influence the behavioral performance of rats injected with Aβ1-42. Furthermore, the BDNF-related improvement in learning was ERK-dependent because the inhibition of ERK, but not JNK or p38, blocked the effects of BDNF on cognitive improvement in rats injected with Aβ1-42. Together, our data suggest that the up-regulation of BDNF in the hippocampus via activation of the ERK signaling pathway can ameliorate Aβ1-42-induced learning deficits, thus identifying a novel pathway through which BDNF protects against AD-related cognitive impairments. The results of this research may shed light on a feasible therapeutic approach to control the progression of AD.
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