Atherosclerosis: Causes and Cures

Atherosclerosis is a systemic disease that occurs due to the formation of Fibro-fatty lesions in arteries that block blood flow. The process of Atherosclerosis is initiated through mechanical, chemical, and immunological activation of the endothelium. Even there are microorganisms involved in the different stages of atherosclerosis. There are a number of molecular factors, RNA’s, macrophages and enzymes that play a vital role in the progression and development of Atherosclerosis that alter the metabolism of Fibro-fatty. Receptors of micro RNA proliferate and regulate endothelial activation and smooth cell Macrophages, monocytes, t-cell and natural killer cells involved in the boosting of the immune system to prevent the atherosclerotic lesion formation. In this review, we can know how RNA’s involved in the pathophysiology side of atherosclerosis and explore the mechanism to regulate Atherosclerosis, and how macrophages evoke an immune response. Therefore, the use of synthetic and natural drugs and following the right diet timely prevent and reduce the risk of development of Atherosclerosis.

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Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL

Nature Medicine ◽

10.1038/nm876 ◽

2003 ◽

Vol 9 (6) ◽

pp. 736-743 ◽

Cited By ~ 507

Author(s):

Christoph J Binder ◽

Sohvi Hörkkö ◽

Asheesh Dewan ◽

Mi-Kyung Chang ◽

Emily P Kieu ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Molecular Mimicry ◽

Oxidized Ldl ◽

Pneumococcal Vaccination ◽

Atherosclerotic Lesion ◽

Lesion Formation ◽

Atherosclerotic Lesion Formation

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Heme Oxygenase-1 Inhibits Atherosclerotic Lesion Formation in LDL-Receptor Knockout Mice

Circulation Research ◽

10.1161/01.res.88.5.506 ◽

2001 ◽

Vol 88 (5) ◽

pp. 506-512 ◽

Cited By ~ 180

Author(s):

Kazunobu Ishikawa ◽

Daisuke Sugawara ◽

Xu-ping Wang ◽

Kazunori Suzuki ◽

Hiroyuki Itabe ◽

...

Keyword(s):

Heme Oxygenase ◽

Knockout Mice ◽

Ldl Receptor ◽

Atherosclerotic Lesion ◽

Heme Oxygenase 1 ◽

Lesion Formation ◽

Ldl Receptor Knockout Mice ◽

Atherosclerotic Lesion Formation

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The onset of atherosclerotic lesion formation in hypercholesterolemic rabbits is delayed by iron depletion

FEBS Letters ◽

10.1016/s0014-5793(99)01199-0 ◽

1999 ◽

Vol 459 (2) ◽

pp. 218-222 ◽

Cited By ~ 35

Author(s):

Durairaj Ponraj ◽

Jagoda Makjanic ◽

Patricia S.P Thong ◽

Benny K.H Tan ◽

Frank Watt

Keyword(s):

Atherosclerotic Lesion ◽

Lesion Formation ◽

Iron Depletion ◽

Atherosclerotic Lesion Formation

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Abstract 83: Bone Marrow Derived Cells Do Not Mediate Reductions in Cholesterol, Atherosclerosis and Adiposity in Microsomal Prostaglindin E Synthase 1 Deficient Mice Fed High Fat Diets Enriched in Cholesterol

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a83 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Sarah Srodulski ◽

Victoria L King

Keyword(s):

Bone Marrow ◽

Weight Gain ◽

Marrow Cell ◽

Atherosclerotic Lesion ◽

Chimeric Mice ◽

High Fat ◽

Lesion Formation ◽

Bone Marrow Derived Cells ◽

Deficient Mice ◽

Atherosclerotic Lesion Formation

Microsomal prostaglandin E 2 synthase-1 (mPGES-1) catalyzes the conversion of COX-2 generated PGH 2 to PGE 2 and is the predominate source of PGE 2 during and inflammatory response. We and others have demonstrated that mPGES-1 deficiency attenuates atherosclerosis in mice on a mixed background. The present study investigated the effect of mPGES-1 deficiency on atherosclerosis in C57BL/6 low density lipoprotein receptor deficient (LDLr-/-) mice. mPGES-1 deficiency attenuated atherosclerosis in LDLr-/- mice fed either a low fat (LF) (P = 0.02) or high fat (HF) (P = 0.0026) diet enriched with cholesterol, or a western diet (P = 0.02) for 17 weeks. mPGES-1 deficiency attenuated weight gain and cholesterol concentrations in mice fed a western (P = 0.004 and P < 0.05; respectively) or HF diet (P = 0.01 and P = 0.012, respectively). However, body weight and cholesterol concentrations were not different in mice fed the LF diet. These data suggest that different mechanisms mediate the reduction in atherosclerosis in mPGES-1 deficient mice fed LF and HF diets. To determine if mPGES-1 deficiency in macrophages contributed to the reduction in atherosclerosis in mice fed HF diets, 4 groups of chimeric mice were generated. Four weeks post bone marrow cell transplant (BMT) mice were fed a western diet. BMT attenuated weight gain in all groups of chimeric mice; however, weight gain was not different between any of the groups. BMT decreased atherosclerotic lesion formation 10 fold in all groups of mice. Neither bone marrow cell specific deficiency of mPGES-1 (KO>WT) or mPGES-1 specific expression in bone marrow derived cells (WT>KO) had an effect on lesion formation compared to WT>WT or KO>KO mice. Cholesterol concentrations were decreased in KO>KO and WT>KO mice compared to WT>WT (P < 0.01) and KO>WT (P< 0.05) mice. These data suggest that mPGES-1 expression in bone marrow derived cells does not contribute to the development of atherosclerosis. Moreover, these data suggest that prostanoids may play a role in hepatic cholesterol homeostasis in mice fed HF diets enriched in cholesterol thereby contributing to atherosclerotic lesion formation. Moreover, these data provide further evidence that prostanoids play a role in regulating the accumulation of diet-induced adiposity.

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Abstract 3710: Estrogen Does not Account for Accelerated Atherosclerosis in LDLr−/− Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_472 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Victoria L King ◽

Nicholas Hatch ◽

Xuan Zhang ◽

Lisa R Tannock

Keyword(s):

Body Weight Gain ◽

Atherosclerotic Lesion ◽

Young Female ◽

Lesion Formation ◽

Accelerated Atherosclerosis ◽

Female Mice ◽

Ldl Particles ◽

Gender Specific Differences ◽

Event Rates ◽

Atherosclerotic Lesion Formation

Clinical studies demonstrate less atherosclerosis in pre-menopausal women compared to age-matched men, but an equalization in atherosclerosis burden and cardiovascular event rates between genders following menopause. Conversely, using the LDLR−/− mouse model we and others have previously demonstrated that young female mice develop accelerated atherosclerosis compared to age matched males. Whether this difference is due to sex hormones or differences in metabolic factors is not clear. To determine if estrogen mediated the alterations in atherosclerosis in the female mice, female mice were ovariectomized (Ovx). Ovx mice had a marked reduction in uterus weight (Sham: 86 ± 1 vs Ovx: 26 ± 1mg, P < 0.001) and both Ovx females and males had greater body weight gain when fed a lard-enriched diet (10% kcal from fat, D12451 , Research Diets) for 17 weeks compared to sham females. Ovariectomy resulted in an increase in fasting glucose concentrations, which was comparable to males. Cholesterol and triglyceride concentrations were higher in both sham and Ovx females compared to males; primarily distributed in increased VLDL and LDL particles. Interestingly, ovariectomy had no significant effect on extent of atherosclerotic lesion formation in female mice and the extent of atherosclerotic lesion area in both female groups was significantly increased compared to male mice. These data suggest that gender specific differences in lipids and atherosclerotic lesion formation in female LDL-R deficient mice fed a diet enriched in lard are not mediated by estrogen.

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Abstract 421: Aldose Reductase Protects Against the Early Atherosclerotic Lesion Formation InApoe-null Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_302-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Sanjay Srivastava ◽

Oleg Barski ◽

Aruni Bhatnagar

Keyword(s):

Lipid Oxidation ◽

Aldose Reductase ◽

Atherosclerotic Lesion ◽

Oxidation Products ◽

Oxidized Lipids ◽

Lesion Formation ◽

Aortic Sinus ◽

Unsaturated Lipids ◽

Lipid Oxidation Products ◽

Atherosclerotic Lesion Formation

Atherosclerotic lesion formation is associated with extensive oxidation of unsaturated lipids and the accumulation of lipid oxidation products. Products of lipid oxidation, particularly aldehydes, stimulate cytokine production and enhance monocyte adhesion. Aldehydes generated by oxidized lipids are metabolized by several biochemical pathways, of which aldose reductase (AR)-catalyzed reduction represents a metabolic fate common to both free and phospholipid esterified aldehydes. Herein, we tested the hypothesis that inhibition of AR could aggravate atherosclerotic lesion formation by preventing the removal and the detoxification of aldehydes generated by oxidized lipids. In atherosclerotic lesions of apoE-null mice, AR protein was associated with macrophage-rich regions and its abundance increased with lesion progression. Treatment of 8 week old apoE-null mice with AR inhibitors sorbinil or tolrestat for 4 weeks increased lesion formation in the aortic arch (P<0.01) and the aortic sinus (P<0.01). No change in lesion formation was observed when 24 week old mice were fed AR inhibitors for 12 weeks. To probe the role of AR in atherogenesis further, we generated AR −/− /apoE −/− mice. Lesions of 8 week old AR −/− /apoE −/− mice maintained on high fat diet for 4 or 12 weeks were significantly larger throughout the aortic tree (P<0.01 for both the groups) when compared with age-matched AR +/+ /apoE −/− mice. Lesions in AR −/− /apoE −/− mice exhibited increased collagen (P<0.01) and macrophage content (P<0.01) and a decrease in smooth muscle cells (P<0.01). GC-MS analysis showed that the concentration of AR substrates HNE and hexanal was increased by 2.5–3 fold (P<0.01) in the plasma of AR −/− /apoE −/− mice as compared with AR +/+ /apoE −/− mice. Immunohistochemical analysis showed greater accumulation of protein-HNE adducts in arterial lesions of AR −/− /apoE −/− mice. These observations suggest that AR is up regulated during atherosclerosis and that this protein protects against early stages of atherosclerotic lesion formation by removing aldehydes generated by lipid oxidation.

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The Endogenous Estradiol Metabolite 2-Methoxyestradiol Reduces Atherosclerotic Lesion Formation in Female Apolipoprotein E-Deficient Mice

Endocrinology ◽

10.1210/en.2007-0259 ◽

2007 ◽

Vol 148 (9) ◽

pp. 4128-4132 ◽

Cited By ~ 27

Author(s):

Johan Bourghardt ◽

Göran Bergström ◽

Alexandra Krettek ◽

Sara Sjöberg ◽

Jan Borén ◽

...

Keyword(s):

Apolipoprotein E ◽

Low Dose ◽

Hormone Replacement ◽

Atherosclerotic Lesion ◽

Total Serum ◽

High Dose ◽

Lesion Formation ◽

Cholesterol Levels ◽

Deficient Mice ◽

Atherosclerotic Lesion Formation

Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17β-estradiol (6 μg/d), or 2-methoxyestradiol [6.66 μg/d (low-dose) or 66.6 μg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo. The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.

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