Evidence suggests that there is an immunological response of the recipient to xenograft bioprosthetic heart valves. Information on the impact of HMG-CoA reductase inhibitors (statins) and their anti-inflammatory properties on bioprosthetic valve failure remains limited. We sought to examine the efficacy of statin therapy in a rodent model of bioprosthetic valve implantation. To mimic the human scenario, fresh or glutaraldehyde-fixed aortic valve root conduits from Lewis rats or Hartley guinea pigs were microsurgically implanted intravascularly into the infra-renal aorta of Lewis rats. The syngeneic control group consisted of a fresh rat valve conduit implanted into a rat. The xenogeneic control group consisted of a glutaraldehyde-fixed guinea pig valve conduit implanted into a rat. Treatment groups consisted of xenogeneic groups treated with either daily steroids or statins. Overall, steroid treatment attenuated the inflammatory response observed within the xenogeneic glutaraldehyde-fixed valve conduits. Treatment with statins did not decrease this inflammatory response.

Cholesterol is an essential component of the cell, but excessive blood levels are a major risk factor for the development of atherosclerotic plaques that can lead to heart disease and stroke, the foremost cause of premature death in Western societies. Policosanol, a mixture of very long chain alcohols derived from sugarcane, has gained considerable attention among the public as safe and effective means to reduce blood cholesterol levels, a belief based on some early clinical studies. My research investigates one possible mechanism by which policosanol might decrease blood cholesterol levels: the inhibition of cholesterol synthesis in the liver. Previous studies with cultured hepatoma cells have indicated that policosanol suppresses HMG-CoA reductase activity, the regulatory step in cholesterol synthesis, by activation of AMP-kinase, which then inactivates HMG-CoA reductase by phosphorylation. My studies have confirmed this activation of AMP-kinase both in hepatoma cells and in whole animals after intragastric administration of policosanol. The present studies were also undertaken to identify the upstream signaling mechanism by which policosanol activates AMP-kinase. Treatment of rat hepatoma cells with policosanol increased the amount of phosphorylated CaMKK, which can directly activate AMP-kinase, but had only a small effect on LKB1, the principal activator of AMP-kinase. Intragastric administration to mice similarly activated CaMKK, but not LKB1, in the liver. To determine if metabolism of policosanol was necessary for activation of AMP-kinase, siRNA-mediated suppression of fatty aldehyde dehydrogenase, fatty acyl CoA synthase-4, or β-ketothiolase in hepatoma cells prevented the phosphorylation of AMP-kinase and HMG-CoA reductase by policosanol, indicating that metabolism of these very long chain alcohols to fatty acids and subsequent peroxisomal β-oxidation is necessary for the suppression of cholesterol synthesis. As the principal product of fatty acid -oxidation is acetyl-CoA, further studies demonstrated that addition of acetate to cells similarly activated AMP-kinase and inactivated HMG-CoA reductase. This finding argues that the activation of AMP-kinase by policosanol results from the generation of excess acetyl-CoA via peroxisomal metabolism. Finally, although the intestine is a significant source of circulating cholesterol, policosanol was unable to activate AMP-kinase in the small intestine. These findings open new perspectives for the control of cholesterol synthesis by activators of AMP-kinase.

Evidence suggests that there is an immunological response of the recipient to xenograft bioprosthetic heart valves. Information on the impact of HMG-CoA reductase inhibitors (statins) and their anti-inflammatory properties on bioprosthetic valve failure remains limited. We sought to examine the efficacy of statin therapy in a rodent model of bioprosthetic valve implantation. To mimic the human scenario, fresh or glutaraldehyde-fixed aortic valve root conduits from Lewis rats or Hartley guinea pigs were microsurgically implanted intravascularly into the infra-renal aorta of Lewis rats. The syngeneic control group consisted of a fresh rat valve conduit implanted into a rat. The xenogeneic control group consisted of a glutaraldehyde-fixed guinea pig valve conduit implanted into a rat. Treatment groups consisted of xenogeneic groups treated with either daily steroids or statins. Overall, steroid treatment attenuated the inflammatory response observed within the xenogeneic glutaraldehyde-fixed valve conduits. Treatment with statins did not decrease this inflammatory response.

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 120-127).

In this study, we examined the effects of thyroid hormone on regulatory processes of cholesterol metabolism. Specifically, the pathways of cholesterol synthesis and cholesterol efflux were investigated. Hepatic HMG-CoA reductase (HMGR) is the rate-limiting enzyme in cholesterol synthesis. Hypothyroid rats exhibit decreased expression of this gene, which can be induced by subsequent treatment with thyroid hormone. The mechanism of this activation was previously unknown. Utilizing in vivo electroporation, we identified HMGR promoter elements necessary for the induction of HMGR by thyroid hormone. The -316/-321 element, the sterol response element, and nuclear factor-y site were all found to be necessary to induce HMGR promoter activity by thyroid hormone. We used electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) studies to demonstrate increased binding of upstream transcription factor-2 (USF-2) to the -316/-321 element in the HMGR promoter in response to thyroid hormone. Finally, co-electroporation of the wild-type HMGR plasmid with siRNA to USF-2, SREBP-2, or NF-Y nearly abolished the T3 induction as measured by promoter activity. Microarray and real-time PCR analysis demonstrated an induction of the apolipoproteins ApoA-I and ApoA-IV mRNA by T3. Serum levels of ApoA-I and ApoA-IV proteins were induced by T3. We collected serum from rats treated with or without T3 and used these sera in an in vitro macrophage efflux model. We found that T3 promoted cholesterol efflux via the ABCA1 cholesterol transporter and not via the ABCG1 transporter. We propose that the induction of serum ApoA-I and ApoA-IV by thyroid hormone promotes cholesterol efflux via the ABCA1 cholesterol transporter. Hepatic ABCG5 and ABCG8 are cholesterol transporters that promote biliary secretion of cholesterol. We utilized EMSAs to scan the shared ABCG5/G8 rat promoter for a thyroid hormone response element (TRE). We identified a TRß binding site at -392/-376 of the ABCG8 promoter. Collectively, these observations provide new insight into the cholesterol-lowering function of thyroid hormone.

Background: In the United States, 30-60% of older adults fall each year; 10-20% of these falls result in injury, hospitalization, or even death. Better prevention of falls in this population may be facilitated by broader identification of risk factors. The use of statins has emerged as a potential risk factor, but the data provide conflicted results. Purpose: To examine the relationship between statin use and falls among community-dwelling older adults. Methods: We evaluated the patient registry of a Level 1 trauma center. All patients aged > 50 years who were admitted for falls in 2015 were included (n=615). Many of these patients had been previously admitted for falls and many were later readmitted for falls. We analyzed predictors of both prior admission and readmission with linear regressions. Independent variables were self-reported balance problems, diagnosis of dementia, and the use of statins. Results: On average, patients admitted for falls were 79.9 + 9.3 years old and 28% (n=173) were taking statins. Our collection of predictors explained 14.2% of the variance in the number of prior admissions (p<0.001). In this model, the use of statins significantly predicted the number of previous fall-related admissions (95% CI: 0.07–0.50, p=0.010). This same model maintained its significance when predicting admissions for future falls (p<0.001) and the use of statins continued to predict a greater number of readmissions (95% CI: 0.04–0.36, p=0.015). Conclusion: More than 25% of all Americans age > 40 years are taking cholesterol-lowering medication; 93% of those medications are statins. Although evidence is conflicted, these data support the finding that statin therapy increases the risk of falls in older adults. Incorporating exercise training as a prophylactic measure: enhancing lipid profiles and decreasing the need for statins while also improving balance, coordination, and mobility, may reduce fall-related injuries.

The objectives of this two part prospective study were to evaluate the effects of statins on C-reactive protein (CRP), butyrylcholinesterase (BChE), lipids, and the relationships between these parameters. Subjects enrolled in this study were separated into two cohorts. The first group (study 1) consisted of 37 subjects converted from pravastatin to cerivastatin. The second group (study 2) consisted of 11 subjects with diabetes initiated on cerivastatin therapy. The subjects were followed for 12-weeks in the Lipid Clinic at David Grant Medical Center at Travis Air Force Base. CRP, BChE, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) were measured at baseline, 6-weeks, and 12-weeks. In study 1, CRP (p = 0.704) and BChE (p = 0.746) remained relatively stable over 12-weeks. The lipid panel changed significantly with TC (p < 0.001) and LDL (p < 0.001) decreasing and HDL (p = 0.017) increasing. Although TG declined numerically, it was not statistically significant (p = 0.649). A significant negative correlation was detected at baseline (r = −0.353, p = 0.032), but lost at 6-weeks and 12-weeks. In study 2, CRP declined by 42.9%, but was not statistically significant (p = 0.178). BChE remained relatively stable over 12-weeks (p = 0.666). TC (p < 0.001) and LDL (p < 0.001) declined and TG (p = 0.035) fluctuated over the course of the study. HDL increased, but it was not statistically significant (p = 0.396). Significant positive correlations were seen between CRP and TG (r = 0.908, p < 0.001) and BChE and TC (r = 0.721, P = 0.012) at baseline and BChE and TG (r = 0.64, p = 0.034) at 12-weeks. These results suggest that statin effects on CRP are independent of the lipid-lowering effects and switching statins may not affect CRP disposition. Cerivastatin does not appear to have effects on BChE activity. Lastly, a possible competitive relationship may exist between CRP and BChE. This is suggested by the negative correlation seen in study 1 and with the gain in correlation between BChE and TG as the correlation was lost between CRP and TG in study 2.

No description available.

HMG-CoA-Reduktasehemmer, sogenannte Statine, und regelmäßige körperliche Aktivität sind mit vermindertem Auftreten zerebrovaskulärer Ereignisse und Zunahme der endothelialen Stickstoffmonoxidsynthase (eNOS) assoziiert. Die Erhöhung der eNOS-mRNA ist mit verbessertem zerebralen Blutfluß und Neuroprotektion bei einer zerebralen Ischämie verbunden. Vor dem Hintergrund, daß Thrombosen und Thrombembolien die häufigste Ursache zerebro- und kardiovaskulärer Ereignisse darstellen, sind NO-vermittelte antithrombotische Effekte jedoch kaum untersucht. Ebenso wenig ist über mögliche Absetzeffekte nach Beendigung einer Statintherapie bekannt. Daher untersuchten wir, ob die Statine Atorva- und Rosuvastatin eNOS-abhängig zu Neuroprotektion führen und verglichen die Effekte mit einem zweiten eNOS-regulierenden Mechanismus: der regelmäßigen körperlichen Aktivität. Dazu quantifizierten wir nach entsprechender Vorbehandlung eNOS auf mRNA- und Proteinebene aus Aorten, Hirngewebe sowie Thrombozyten und bestimmten die Läsionsvolumina im experimentellen Schlaganfallmodell. Außerdem untersuchten wir nach Statingabe Thrombozytenfunktionsparameter sowie Blutungszeit und Thrombusformation in vivo. Zwei bzw. vier Tage nach Absetzen der Statinbehandlung wiederholten wir die eNOS-Messungen, Schlaganfallexperimente und Gerinnungsanalysen. Wir fanden nach Statinvorbehandlung cholesterinunabhängig eine Zunahme der eNOS, was mit Neuroprotektion im Schlaganfallmodell und verminderter Gerinnungsaktivität verbunden war. Nach Absetzen der Behandlung kam es jedoch zu einer drastischen Abnahme der eNOS, was mit deutlichem Anstieg der Thrombozytenmarker im Plasma und schnellem Verlust der beobachteten positiven Effekte auf Läsionsgröße und Gerinnungssystem einherging. Regelmäßige körperliche Aktivität führt ebenfalls eNOS-abhängig zu verbessertem zerebralen Blutfluß und kleineren Läsionsvolumina bei zerebraler Ischämie. Diese Ergebnisse sind mit den Daten nach Statingabe vergleichbar. Wir demonstrieren einen Klasseneffekt der Statine für eNOS-vermittelte Neuroprotektion im zerebralen Ischämiemodell. Durch die zusätzliche gerinnungshemmende Wirkung könnte diese Wirkstoffklasse neue Ansätze zur prophylaktischen Schlaganfallbehandlung unabhängig vom Cholesterinspiegel eröffnen. Ein Absetzen der Statinbehandlung kann jedoch zu einer Zunahme der Schlaganfallgröße führen und sollte möglicherweise bei Risikopatienten vermieden werden. Regelmäßiges körperliches Training führt zu vergleichbarer Erhöhung der eNOS sowie Neuroprotektion und bietet damit eine sinnvolle Verknüpfung aus prophylaktischer Schlaganfallbehandlung und Rehabilitation. / HMG-CoA-reductase inhibitors, so called statins and regular physical activity are associated with less cerebrovascular events and increase of endothelial nitric oxide synthase (eNOS). Raise of eNOS-mRNA results in cerebral blood flow (CBF) augmentation which refers neuroprotection after ischemic stroke. It is known that thromboses cause the most cerebrovascular events, but nitric oxide (NO) dependent antithrombotic effects are poor examined. In addition there are little information about effects after withdrawal of statin treatment. That is why we investigated Atorva- and Rosuvastatin regarding eNOS dependent neuroprotection and compared the effects with regular physical activity, the second eNOS enhancing mechanism. Therefore after corresponding pretreatment we quantified eNOS-mRNA and protein from aortas, brain tissue and thrombocytes and determined lesion volume after experimental middle cerebral artery occlusion (MCAo). Furthermore after statin treatment we measured marker of thrombocyte activation, as well as bleeding time and thrombus formation in vivo. Two and four days after withdrawal of statin treatment we repeated eNOS measurements, neuroprotection studies and coagulation analyses. We found eNOS upregulation independent from serum cholesterol level after statin pretreatment and this was associated with neuroprotection after ischemic stroke and decreased platelet activation. But after withdrawal of statin treatment eNOS expression was downregulated, which went along with clear upregulation of platelet activation and a rapid loss of the observed positive effects on lesion volume and hemostasis. Regular physical activity leads to an increase of eNOS, which we could correlate with CBF augmentation and improved outcome after MCAo. These results were comparable to the data after statin treatment. We demonstrate a class effect of statins for eNOS-dependent neuroprotection in our ischemia modell. Because of the additional antithrombotic effects statins may present a new approach to prophylactic stroke treatment independent from cholesterol level. Withdrawal of statin treatment may refer increased cerebral lesion volume and should be avoided in patients with risk for cerebrovascular events. Regular physical activity results in comparable eNOS dependent neuroprotection and offers a useful combination between prophylactic stroke treatment and rehabilitation.

Diversos estudos epidemiológicos mostram que nutrientes e outros compostos bioativos presentes nos alimentos (CBA) apresentam atividade quimiopreventiva contra o câncer. Assim, destaca-se o estudo dos isoprenóides devido a sua ação promissora tanto na prevenção quanto na terapia do câncer. Todavia, apesar dessas evidências, pouco se sabe a respeito da ação dessas substâncias nos processos de proliferação celular e apoptose in vivo. Assim, 141 ratos Wistar foram tratados durante duas semanas consecutivas com farnesol (grupo FR, 25 mg/100 g de peso corporal) ou óleo de milho (grupo OM; controle, 0,25 mL/100 g de peso corporal) e sacrificados em diferentes momentos após a hepatectomia parcial (HP; 0 h, 30 min, 2 h, 4 h, 8 h, 12 h, 18 h e 24 h). Os parâmetros hepáticos analisados foram a proliferação celular (núcleos marcados para PCNA/mm2), apoptose (corpúsculos apoptóticos [CA\'s] por mm2) e expressão de p65, ciclina D1 (\"western blot\") e HMG-CoA redutase (\"dot-blot\"). Os animais tratados com o isoprenóide, assim como o grupo controle, apresentaram reduzida taxa de proliferação celular até 8h após a cirurgia. No entanto, a partir desse momento, o grupo FR passou a apresentar taxa de proliferação celular inferior ao grupo OM, diferença esta que atingiu significância estatística (p<0,05) 24h após a HP. Com relação a apoptose, animais tratados com FR apresentaram maior número de CA\'s (p<0,05) do que o grupo OM 30 min após a HP. Já em relação à ação do FR em âmbito molecular, houve uma redução de 40% e 50% na expressão de p65 e ciclina D1 30min e 24h após a HP, respectivamente, embora essas diferenças não tenham atingido significância estatística (p>0,05). Além disso, animais tratados com o isoprenóide apresentaram maior (p<0,05) expressão do gene que codifica para HMG-CoA redutase 2 h e 12 h após a cirurgia. Assim, tanto a inibição da proliferação celular quanto a indução de apoptose podem ser reflexo das alterações da expressão hepática dos genes para HMG-CoA redutase, p65 e ciclina D1 por parte do isoprenóide. / Epidemiological data have shown that nutrients and others bioactive compounds in food have chemopreventive activities against cancer. Among these compounds, isoprenoids are suggested either as a chemopreventive or chemotherapy agents. However, despite these evidences, studies focused on the isoprenoids activities on cell proliferation and apoptosis in vivo are rare. Thus, the effect of the 15-carbon isoprenoid farnesol on liver regeneration after partial hepatectomy was evaluated. Wistar rats were treated for two consecutive weeks with farnesol (FR group, 25 mg/100 g body weight) or corn oil (OM group, control, 0,25 mL/100 g body weight) and killed at different time points after partial hepatectomy (HP; 0 h, 30 min, 2 h, 4 h, 8 h, 12 h, 18 h and 24 h). Still, hepatic cell proliferation (PCNA lebeled nuclei), apoptosis (quantification of apoptotic bodies), p65 and cyclin D1 protein expression (western blot) and HMG-CoA reductase mRNA expression (dot blot) were also evaluated. Comparing to OM group, farnesol treatment significantly inhibited (p<0,05) hepatic cell proliferation 24 h after HP. Regarding apoptosis, also compared to controls, farnesol treated rats presented more (p<0,05) apoptotic bodies at 30 min. Besides, there were a suggestion of a higher number of apoptotic bodies 2 and 12 hours after HP in FR group comparing to OM group. According to western blot analysis, comparing to controls, this 15-carbon isoprenoid reduced 40% and 50% p65 and cyclin D1 hepatic protein expression, 30 min and 24 h after partial hepatectomy, respectively, although the differences did not also reach the statistical significance. Furthermore, farnesol treated rats had higher (p<0,05) HMG-CoA reductase mRNA levels than controls 2 h and 12 h after the surgery. Theses data suggest that the alterations on p65, cyclin D1 and HMG¬-CoA reductase gene expression observed in FR group might be associated with the inhibition of cell proliferation and the induction of apoptosis by farnesol.