Effect of Oxysterol-Induced Apoptosis of Vascular Smooth Muscle Cells on Experimental Hypercholesterolemia

Perales, Sonia; Alejandre, M.J.; Palomino-Morales, Rogelio; Torres, Carolina; Iglesias, J.; Linares, Ana María

doi:10.1155/2009/456208

Cited by 17 publications

(16 citation statements)

References 46 publications

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“…A marked increase in Bax protein levels was also observed, possibly mediated by p53 [35]. These results indicate that, under our experimental conditions, 25-HC-induced apoptosis is mediated by p53.…”

Section: Discussionsupporting

confidence: 65%

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Fish oil supplementation reverses the effect of cholesterol on apoptotic gene expression in smooth muscle cells

et al. 2010

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BackgroundNutritional control of gene regulation guides the transformation of smooth muscle cells (SMC) into foam cells in atherosclerosis. Oxidative stress has been reported in areas of lipid accumulation, activating proliferation genes. Suppression of oxidative stress by antioxidant administration reduces this activation and the progression of lesions. We hypothesized that fish oil consumption may protect against atherosclerotic vascular disease. The study objective was to determine the effects of dietary cholesterol and fish-oil intake on the apoptotic pathways induced by 25-hydroxycholesterol (25-HC) in SMC cultures.MethodsAn in vivo/in vitro cell model was used, culturing SMC isolated from chicks exposed to an atherogenic cholesterol-rich diet with 5% of cholesterol (SMC-Ch) alone or followed by an anti-atherogenic fish oil-rich diet with 10% of menhaden oil (SMC-Ch-FO) and from chicks on standard diet (SMC-C). Cells were exposed to 25-HC, studying apoptosis levels by flow cytometry (Annexin V) and expressions of caspase-3, c-myc, and p53 genes by quantitative real-time reverse transcriptase-polymerase chain reaction. Results: Exposure to 25-HC produced apoptosis in all three SMC cultures, which was mediated by increases in caspase-3, c-myc, and p53 gene expression. Changes were more marked in SMC-Ch than in SMC-C, indicating that dietary cholesterol makes SMC more susceptible to 25-HC-mediated apoptosis. Expression of p53 gene was elevated in SMC-Ch-FO. This supports the proposition that endogenous levels of p53 protect SMC against apoptosis and possibly against the development of atherosclerosis. Fish oil attenuated the increase in c-myc levels observed in SMC-C and SMC-Ch, possibly through its influence on the expression of antioxidant genes.ConclusionReplacement of a cholesterol-rich diet with a fish oil-rich diet produces some reversal of the cholesterol-induced changes, increasing the resistance of SMC to apoptosis.

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Section: Discussionsupporting

confidence: 65%

“…We previously characterized 25OHC-induced SMC apoptosis by studying antiapoptotic and proapoptotic (bcl-2, bcl-xl and bax) gene expression [35]. The objective of the present study was to characterize 25-HC-induced SMC apoptosis by studying of caspase-3, c-myc, and p53 gene expression in SMC-C, SMC-Ch, and SMC-Ch-FO cultures.…”

Section: Introductionmentioning

confidence: 96%

Fish oil supplementation reverses the effect of cholesterol on apoptotic gene expression in smooth muscle cells

et al. 2010

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“…Hypercholesterolemia has also been shown to modulate apoptosis in other tissue types. For example, Perales et al showed upregulated BAX expression in vascular smooth muscle cells exposed to 25-hydroxycholesterol [41]. Therefore, the majority of these results demonstrates that there is a strong relationship between increased cardiac apoptosis and hypercholesterolemia, although different models of hypercholesterolemia display varying constellations of altered apoptotic markers.…”

Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia downregulates autophagy in the rat heart

et al. 2017

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BackgroundWe have previously shown that efficiency of ischemic conditioning is diminished in hypercholesterolemia and that autophagy is necessary for cardioprotection. However, it is unknown whether isolated hypercholesterolemia disturbs autophagy or the mammalian target of rapamycin (mTOR) pathways. Therefore, we investigated whether isolated hypercholesterolemia modulates cardiac autophagy-related pathways or programmed cell death mechanisms such as apoptosis and necroptosis in rat heart.MethodsMale Wistar rats were fed either normal chow (NORM; n = 9) or with 2% cholesterol and 0.25% cholic acid-enriched diet (CHOL; n = 9) for 12 weeks. CHOL rats exhibited a 41% increase in plasma total cholesterol level over that of NORM rats (4.09 mmol/L vs. 2.89 mmol/L) at the end of diet period. Animals were sacrificed, hearts were excised and briefly washed out. Left ventricles were snap-frozen for determination of markers of autophagy, mTOR pathway, apoptosis, and necroptosis by Western blot.ResultsIsolated hypercholesterolemia was associated with a significant reduction in expression of cardiac autophagy markers such as LC3-II, Beclin-1, Rubicon and RAB7 as compared to controls. Phosphorylation of ribosomal S6, a surrogate marker for mTOR activity, was increased in CHOL samples. Cleaved caspase-3, a marker of apoptosis, increased in CHOL hearts, while no difference in the expression of necroptotic marker RIP1, RIP3 and MLKL was detected between treatments.ConclusionsThis is the first comprehensive analysis of autophagy and programmed cell death pathways of apoptosis and necroptosis in hearts of hypercholesterolemic rats. Our data show that isolated hypercholesterolemia suppresses basal cardiac autophagy and that the decrease in autophagy may be a result of an activated mTOR pathway. Reduced autophagy was accompanied by increased apoptosis, while cardiac necroptosis was not modulated by isolated hypercholesterolemia. Decreased basal autophagy and elevated apoptosis may be responsible for the loss of cardioprotection reported in hypercholesterolemic animals.

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“…The data led us to suppose that the major contributor to apoptosis in ischaemic‐reperfused myocardium is the oxidative stress originating from blood or non‐myocytes. Thus, we examined cells incubated with 25‐OH‐cholesterol, which can be involved in atherosclerosis, one of the main causes of myocardial infarction (Perales et al, 2009). It was chosen as an example of oxygenated derivative of cholesterol that may be formed in vivo during reperfusion as a direct result of the increased oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte apoptosis in ischaemia‐reperfusion due to the exogenous oxidants at the time of reperfusion

Rosca¹,

Matei²,

Dragan³

et al. 2012

Cell Biology International

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Various studies performed on different models have demonstrated that apoptosis occurs in ischaemic-reperfused myocardium in vivo; however, the individual contribution of ischaemia and reperfusion to CMC (cardiomyocyte) apoptosis remains uncertain. We have determined the main inducer of CMC apoptosis in ischaemia-reperfusion by exposing CMCs to either 30 min ischaemia followed by reperfusion or to 25-OH-cholesterol (25-hydroxycholesterol) for 1-3 days. Both ischaemia-reperfusion and exogenous oxidants increased the Bax/Bcl-2 ratio, a favourable effect for the apoptotic process. However, apoptosis was not observed in ischaemic CMCs in the absence of reperfusion. Moreover, reperfusion after 30 min ischaemia did not make an important contribution to CMC apoptosis in culture in terms of caspase 3 activation. In contrast, 25-OH-cholesterol promoted CMC apoptosis by a caspase 3-dependent mechanism that involved the transcriptional activation of the pro-apoptotic protein, Bax and post-translational degradation of the anti-apoptotic protein, Bcl-2. From these results, we conclude that CMC apoptosis is not induced by ischaemia per se, but by the oxidants from the surrounding environment at the time of reperfusion. These exogenous oxidants exacerbate the alterations induced by ischaemia and complete the apoptotic process at the time when ATP and glucose levels are restored.

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Effect of Oxysterol-Induced Apoptosis of Vascular Smooth Muscle Cells on Experimental Hypercholesterolemia

Cited by 17 publications

References 46 publications

Fish oil supplementation reverses the effect of cholesterol on apoptotic gene expression in smooth muscle cells

Fish oil supplementation reverses the effect of cholesterol on apoptotic gene expression in smooth muscle cells

Hypercholesterolemia downregulates autophagy in the rat heart

Cardiomyocyte apoptosis in ischaemia‐reperfusion due to the exogenous oxidants at the time of reperfusion

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