Mechanism of aortic medial matrix remodeling is distinct in patients with bicuspid aortic valve

ObjectivesPatients with bicuspid aortic valves (BAV) are predisposed to developing ascending thoracic aortic aneurysms (TAA) at an earlier age than patients who develop degenerative TAAs and have a tricuspid aortic valve (TAV). The hypothesis tested is that BAV-associated aortopathy is mediated by a mechanism of matrix remodeling that is distinct from that seen in TAAs of patients with tricuspid aortic valves.MethodsAortic specimens were collected during ascending aortic replacement, aortic valve replacement, and heart transplants from nonaneurysmal (NA) donors and recipients. Matrix architecture of the aortic media was assessed qualitatively using multiphoton microscopy followed by quantification of collagen and elastin fiber orientation. α-Elastin was determined and matrix maturity was assessed by quantifying immature and mature collagen and lysyl oxidase (Lox) expression and activity in aortic specimens. Matrix metalloproteinase-2/9 activity was quantified in aortic smooth muscle cells.ResultsElastin and collagen fibers were more highly aligned in BAV-NA and BAV-TAA cases than in TAV-TAA cases, whereas TAV-TAA cases were more disorganized than TAV-NA cases. α-Elastin content was unchanged. Immature collagen was reduced in BAV-NA and BAV-TAA cases when compared with TAV-NA and TAV-TAA cases. Mature collagen was elevated in TAV-TAA cases compared with TAV-NA and BAV-TAA cases. There was a trend toward elevated Lox gene expression and activity and matrix metalloproteinase-2/9 activity for TAV-TAA, BAV-NA, and BAV-TAA specimens.ConclusionsThe highly aligned matrix architecture in patients with BAVs indicates that wall remodeling is distinct from TAV-TAA. Altered matrix architecture and reduced collagen maturity suggest that the effector molecules mediating the remodeling of TAAs are different in BAV and TAV cases

Pharmacological blockade of corticotropin-releasing hormone receptor 1 (CRH1R) reduces voluntary consumption of high alcohol concentrations in non-dependent Wistar rats.

A dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in the development of excessive alcohol consumption and dependence. The aim of the present study was to evaluate whether the CRH system is also recruited when non-dependent Wistar rats escalate to high alcohol intake in the intermittent (alternate days) model of drinking. METHODS: We compared intermittent and continuous access to 20% (v/v) alcohol in a two-bottle free choice drinking paradigm. Following a total of twenty 24-hour exposures for every experimental group, we assessed signs of alcohol withdrawal, including anxiety-like behavior and sensitivity to stress. The selective CRH1 receptor (CRH1R) antagonist antalarmin (0, 10, 20 mg/kg, i.p.) was tested on alcohol consumption. RESULTS: Intermittent access to 20% alcohol led non-selected Wistar rats to escalate their voluntary intake to a high and stable level, whereas continuously exposed animals maintained a lower consumption. These groups did not differ in physical withdrawal signs. In addition, no differences were found when anxiogenic-like behavior was studied, neither under basal conditions or following restraint stress. Nevertheless, sensitivity to the treatment with the CRH1R antalarmin was observed since a reduction of 20% alcohol intake was found in both groups of animals regardless of the regimen of alcohol exposure. In addition, antalarmin was effective when injected to animals exposed to intermittent 10% (v/v) alcohol whereas it failed to suppress 10% continuous alcohol intake. CONCLUSIONS: Pharmacological blockade of CRH1R reduced alcohol drinking when sustained high levels of intake were achieved suggesting that the CRH system plays a key role when high doses of ethanol are consumed by non-dependent subjects. This supports the notion that CRH system not only maintains the dependent state but also engages the transition to dependence

Long-term suppression of forebrain neurogenesis and loss of neuronal progenitor cells following prolonged alcohol dependence in rats.

Alcohol dependence leads to persistent neuroadaptations, potentially related to structural plasticity. Previous work has shown that hippocampal neurogenesis is modulated by alcohol, but effects of chronic alcohol on neurogenesis in the forebrain subventricular zone (SVZ) have not been reported. Effects in this region may be relevant for the impairments in olfactory discrimination present in alcoholism. Here, we examined the effects of prolonged alcohol dependence on neurogenesis. Rats were sacrificed directly after 7 wk of intermittent alcohol vapour exposure, or 3, 7 or 21 d into abstinence. Proliferation was assessed using BrdU and Ki67 immunoreactivity, newly differentiated neurons (neurogenesis) as doublecortin-immunoreactivity (DCX-IR), and neural stem cells using the SOX2 marker. In the dentate gyrus, chronic dependence resulted in a pattern similar to that previously reported for acute alcohol exposure: proliferation and neurogenesis were suppressed by the end of exposure, rebounded on day 3 of abstinence, and returned to control levels by days 7 and 21. In the SVZ, proliferation was also suppressed at the end of alcohol exposure, followed by a proliferation burst 3 d into abstinence. However, in this area, there was a trend for reduced proliferation on days 7 and 21 of abstinence, and this was accompanied by significant suppression of DCX-IR, indicating a long-term suppression of forebrain neurogenesis. Finally, a decrease in the SOX2 stem cell marker was detected at days 7 and 21, suggesting long-term reduction of the SVZ stem cell pool. While suppression of hippocampal neurogenesis by alcohol dependence is transient, the suppression in the forebrain SVZ appears long-lasting

LONG-LASTING SUPPRESSION OF SUBVENTRICULAR ZONE NEUROGENESIS FOLLOWING A HISTORY OF ETHANOL DEPENDENCE

Exposure to repeated cycles of ethanol intoxication and withdrawal results in a well characterized persistent post-dependent increase in excessive voluntary ethanol consumption and behavioral sensitivity to stress. We have previously described some molecular neuroadaptations that contribute to these behavioral traits. Formation of new neurons in the adult brain, or adult neurogenesis, is related to stress responsiveness, and previous work has established that it is modulated by ethanol intoxication and withdrawal. Here, we asked whether adult neurogenesis is altered in the post-dependent state, in a manner that could contribute to the functional phenotype observed in this condition. To this end, we studied cell proliferation and neurogenesis in the subgranular zone of the dentate gyrus (SGZ) and in the subventricular zone lining the lateral ventricle (SVZ) in rats over a period of 3 weeks following a previously described 7 week intermittent ethanol vapor exposure to induce dependence, and compared to controls without a history of ethanol exposure. A single dose of 5-bromo-2-deoxyuridine (BrdU, 200 mg/kg, i.p.) was administered 4-5 h prior to euthanasia on day 0, 3, 7 and 21 post induction of dependence (abstinence days). Proliferating precursor cells incorporate the mitotic marker BrdU and were identified using immunohistochemistry in SVZ and SGZ. In agreement with prior work, ethanol exposure decreased density and number of proliferating cells by 70 % in both the SVZ (p<0.001) and SGZ (p<0.05), followed by a 2- fold rebound burst in proliferation on day 3 (p<0.001) of abstinence. In the SGZ, proliferation returned to normal levels within one week. However, the density of proliferating cells in the SVZ remained significantly decreased on day 7 (36%, p<0.01) and day 21 (35%, p<0.05) of abstinence. These changes were paralleled by decreased doublecortin expression, a neuronal marker expressed shortly after neuronal cell fate determination. Our data indicate a long-lasting suppression of neurogenesis in the SVZ of post-dependent rats, potentially leading to reduced neuronal turnover in the olfactory bulb and possibly also in prefrontal cortex circuitry. Although, the functional correlates of SVZ suppression are unknown, loss of olfactory discrimination is common in alcoholics and correlates with loss of executive function