S-EPMC4475013 - Pharmacological Treatment with Annexin A1 Reduces Atherosclerotic Plaque Burden in LDLR-/- Mice on Western Type Diet. - OmicsDI

Unknown

Dataset Information

Pharmacological Treatment with Annexin A1 Reduces Atherosclerotic Plaque Burden in LDLR-/- Mice on Western Type Diet.

ABSTRACT:

Objective

To investigate therapeutic effects of annexin A1 (anxA1) on atherogenesis in LDLR-/- mice.

Methods

Human recombinant annexin A1 (hr-anxA1) was produced by a prokaryotic expression system, purified and analysed on phosphatidylserine (PS) binding and formyl peptide receptor (FPR) activation. Biodistribution of 99mTechnetium-hr-anxA1 was determined in C57Bl/6J mice. 12 Weeks old LDLR-/- mice were fed a Western Type Diet (WTD) during 6 weeks (Group I) or 12 weeks (Group P). Mice received hr-anxA1 (1 mg/kg) or vehicle by intraperitoneal injection 3 times per week for a period of 6 weeks starting at start of WTD (Group I) or 6 weeks after start of WTD (Group P). Total aortic plaque burden and phenotype were analyzed using immunohistochemistry.

Results

Hr-anxA1 bound PS in Ca2+-dependent manner and activated FPR2/ALX. It inhibited rolling and adherence of neutrophils but not monocytes on activated endothelial cells. Half lives of circulating 99mTc-hr-anxA1 were <10 minutes and approximately 6 hours for intravenously (IV) and intraperitoneally (IP) administered hr-anxA1, respectively. Pharmacological treatment with hr-anxA1 had no significant effect on initiation of plaque formation (-33%; P = 0.21)(Group I) but significantly attenuated progression of existing plaques of aortic arch and subclavian artery (plaque size -50%, P = 0.005; necrotic core size -76% P = 0.015, hr-anxA1 vs vehicle) (Group P).

Conclusion

Hr-anxA1 may offer pharmacological means to treat chronic atherogenesis by reducing FPR-2 dependent neutrophil rolling and adhesion to activated endothelial cells and by reducing total plaque inflammation.

SUBMITTER: Kusters DH

PROVIDER: S-EPMC4475013 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

altmetric image

Publications

Pharmacological Treatment with Annexin A1 Reduces Atherosclerotic Plaque Burden in LDLR-/- Mice on Western Type Diet.

Kusters Dennis H M DH Chatrou Martijn L ML Willems Brecht A G BA De Saint-Hubert Marijke M Bauwens Matthias M van der Vorst Emiel E Bena Stefania S Biessen Erik A L EA Perretti Mauro M Schurgers Leon J LJ Reutelingsperger Chris P M CP

PloS one 20150619 6

<h4>Objective</h4>To investigate therapeutic effects of annexin A1 (anxA1) on atherogenesis in LDLR-/- mice.<h4>Methods</h4>Human recombinant annexin A1 (hr-anxA1) was produced by a prokaryotic expression system, purified and analysed on phosphatidylserine (PS) binding and formyl peptide receptor (FPR) activation. Biodistribution of 99mTechnetium-hr-anxA1 was determined in C57Bl/6J mice. 12 Weeks old LDLR-/- mice were fed a Western Type Diet (WTD) during 6 weeks (Group I) or 12 weeks (Group P). ...[more]

Similar Datasets

Project description:BackgroundNonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative.MethodsWe evaluated the efficacy of two diets, a non-purified chow (NP) and purified (low-fat low-cholesterol, LFLC) diet to reverse western diet (WD)-induced NASH and fibrosis in Ldlr-/- mice.ResultsMice fed WD for 22-24 weeks developed robust hepatosteatosis with mild fibrosis, while mice maintained on the WD an additional 7-8 weeks developed NASH with moderate fibrosis. Returning WD-fed mice to the NP or LFLC diets significantly reduced body weight and plasma markers of metabolic syndrome (dyslipidemia, hyperglycemia) and hepatic gene expression markers of inflammation (Mcp1), oxidative stress (Nox2), fibrosis (Col1A, LoxL2, Timp1) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic Col1A1 mRNA were rapidly reduced following the switch from the WD to the LFLC diet. However, hepatic triglyceride content and fibrosis did not return to normal levels 8 weeks after the change to the LFLC diet. Time course studies further revealed a strong association (r2 ≥ 0.52) between plasma markers of inflammation (TLR2 activators) and hepatic fibrosis markers (Col1A, Timp1, LoxL2). Inflammation and fibrosis markers were inversely associated (r2 ≥ 0.32) with diet-induced changes in hepatic ω3 and ω6 polyunsaturated fatty acids (PUFA) content.ConclusionThese studies establish a temporal link between plasma markers of inflammation and hepatic PUFA and fibrosis. Low-fat low-cholesterol diets promote reversal of many, but not all, features associated with WD-induced NASH and fibrosis in Ldlr-/- mice.

Project description:ObjectivesEpidemiological and experimental evidence have indicated potential health benefits of vitamin E supplementation on coronary heart disease (CHD), but several clinical trials have reported no benefit from vitamin E supplementation on CHD. We hypothesized that supplemental intake of vitamin E from an early age may prevent or retard the development and progression of atherosclerosis and CHD mortality.MethodsTo test this hypothesis, 300 Ldlr(-/-) mice were divided into groups receiving Western style high fat/cholesterol (HFHC), moderate fat/cholesterol (MFMC), or low fat/cholesterol (LFLC) diets all containing 50 IU of vitamin E. These dietary groups were further subdivided into four sub-groups (n = 25) receiving their respective diets with no vitamin E supplementation or additionally supplemented with vitamin E (500 IU/kg diet) starting at the early age of 5 wks, or 6 mo, or 12 mo. All mice remained on their assigned diets until age 18 mo. Body weight, health status and survival rate of mice were monitored and recorded. After 18 mo of dietary treatments, mice were sacrificed.ResultsBody weight was the highest in HFHC groups and the lowest in LFLC groups. Plasma concentration of cholesterol and triglycerides was high in all dietary groups, and plasma vitamin E was high in vitamin E supplemented groups. Fifty percent of mice fed Western style HFHC diet and 53% of mice fed MFMC diet survived during the 18 mo, whereas 75% of mice fed LFLC diet survived during the 18 mo dietary treatments. At the age of 18 mo, all the Ldlr(-/-) mice, regardless of dietary treatments, had several advanced atherosclerotic lesions in both aortic root and aortic tree. Within the LFLC groups, those that received vitamin E supplements from age 5 wks up to 18 mo had a significantly higher survival rate of 88% (p = 0.04) and lower mortality (12%) compared to mice that did not receive vitamin E supplements (64%). This lower mortality rate and higher survival rate coincided with significantly (p = 0.03) fewer aortic lesions in the vitamin E supplemented LFLC group (50%) compared to LFLC mice that did not receive vitamin E supplements in their diets (65%). Subjective immunohistochemical evaluation of aortic valves showed that LFLC mice that received vitamin E supplements for 18 mo had less intima media thickness compared to LFLC mice that did not receive vitamin E supplements in their diet. The LFLC mice that were supplemented with vitamin E for 18 mo had the lowest mRNA expression of inflammatory markers such as VCAM-1, MCP-1 and CD36 in samples obtained from lesion and non-lesionareas.ConclusionIn conclusion, 500 mg vitamin E/kg diet in Ldlr(-/-) mice is not effective at reducing mortality and atherosclerosis when the diet contained high or medium levels of fat and cholesterol. However, a relatively low dose and long-term vitamin E supplementation started from an early age is effective in reducing mortality and atherosclerotic lesions in genetically prone Ldlr(-/-) mice fed LFLC diet.