Quercetin Prevents Diastolic Dysfunction Induced by a High-Cholesterol Diet: Role of Oxidative Stress and Bioenergetics in Hyperglycemic Rats.
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SUBMITTER: Castillo RL
PROVIDER: S-EPMC5821945 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Overnutrition and insulin resistance are especially prominent risk factors for the development of cardiac diastolic dysfunction in females. We recently reported that consumption of a Western diet (WD) containing excess fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) for 16 weeks resulted in cardiac diastolic dysfunction and aortic stiffening in young female mice and that these abnormalities were prevented by mineralocorticoid receptor blockade. Herein, we extend those studies by testing whether WD-induced diastolic dysfunction and factors contributing to diastolic impairment, such as cardiac fibrosis, hypertrophy, inflammation, and impaired insulin signaling, are modulated by excess endothelial cell mineralocorticoid receptor signaling. Four-week-old female endothelial cell mineralocorticoid receptor knockout and wild-type mice were fed mouse chow or WD for 4 months. WD feeding resulted in prolonged relaxation time, impaired diastolic septal wall motion, and increased left ventricular filling pressure indicative of diastolic dysfunction. This occurred in concert with myocardial interstitial fibrosis and cardiomyocyte hypertrophy that were associated with enhanced profibrotic (transforming growth factor β1/Smad) and progrowth (S6 kinase-1) signaling, as well as myocardial oxidative stress and a proinflammatory immune response. WD also induced cardiomyocyte stiffening, assessed ex vivo using atomic force microscopy. Conversely, endothelial cell mineralocorticoid receptor deficiency prevented WD-induced diastolic dysfunction, profibrotic, and progrowth signaling, in conjunction with reductions in macrophage proinflammatory polarization and improvements in insulin metabolic signaling. Therefore, our findings indicate that increased endothelial cell mineralocorticoid receptor signaling associated with consumption of a WD plays a key role in the activation of cardiac profibrotic, inflammatory, and growth pathways that lead to diastolic dysfunction in female mice.
| S-EPMC4644106 | biostudies-literature
Project description:Although women are more susceptible to pulmonary arterial hypertension (PAH) than men, their right ventricular (RV) function is better preserved. Estrogen receptor-α (ERα) has been identified as a likely mediator for estrogen protection in the RV. However, the role of ERα in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ERα removes female protection from adverse remodeling and is permissive for the development of a maladapted RV phenotype. Male and female rats with a loss-of-function mutation in ERα (ERαMut) and wild-type (WT) littermates underwent RV pressure overload by pulmonary artery banding (PAB). At 10 wk post-PAB, WT and ERαMut demonstrated RV hypertrophy. Analysis of RV pressure waveforms demonstrated RV-pulmonary vascular uncoupling and diastolic dysfunction in female, but not male, ERαMut PAB rats. Similarly, female, but not male, ERαMut exhibited increased RV fibrosis, comprised primarily of thick collagen fibers. There was an increased protein expression ratio of TIMP metallopeptidase inhibitor 1 (Timp1) to matrix metalloproteinase 9 (Mmp9) in female ERαMut compared with WT PAB rats, suggesting less collagen degradation. RNA-sequencing in female WT and ERαMut RV revealed kallikrein-related peptidase 10 (Klk10) and Jun Proto-Oncogene (Jun) as possible mediators of female RV protection during PAB. In summary, ERα in females is protective against RV-pulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ERα appears to be dispensable for RV adaptation in males. ERα may be a mediator of superior RV adaptation in female patients with PAH.NEW & NOTEWORTHY Using a novel loss-of-function mutation in estrogen receptor-α (ERα), we demonstrate that female, but not male, ERα mutant rats display right ventricular (RV)-vascular uncoupling, diastolic dysfunction, and fibrosis following pressure overload, indicating a sex-dependent role of ERα in protecting against adverse RV remodeling. TIMP metallopeptidase inhibitor 1 (Timp1), matrix metalloproteinase 9 (Mmp9), kallikrein-related peptidase 10 (Klk10), and Jun Proto-Oncogene (Jun) were identified as potential mediators in ERα-regulated pathways in RV pressure overload.
| S-EPMC7792707 | biostudies-literature
Project description:BackgroundComparable to commercial expensive high-fat diets, cholesterol-cholate-butterfat (CCB) diet has also been used to induce hyperlipidemia in rats. Our objective was to explore its influence on multiple organs. Consequence of fasting was also analysed.MethodsRats in groups 1 and 2 received normal diet (ND) whereas groups 3 and 4 received CCB-diet. Food was withdrawn daily for two hours from groups 2 (ND-F) and 4 (CCB-F). Blood was collected at fourth and sixth week for biochemical estimation; Morris water maze was done in the sixth week for learning ability and memory; after which aortae were isolated for vascular reactivity.ResultsApart from hyperlipidemia, CCB also induced hyperglycemia with marked increase in hepatic enzymes: gamma-glutamyl transferase (GGT), alanine and aspartate aminotransferase (ALT and AST); and vascular biomarkers: uric acid (UA), phosphorus and alkaline phosphatase (ALP). Isolated aortae, pre-contracted with phenylephrine, were less responsive to acetylcholine indicating endothelial dysfunction--serum nitric oxide (NO) production was limited with subsequent inhibition of endothelial NO synthase. CCB diet also compromised learning ability. CCB-coupled fasting potentiated hyperlipidemia but prevented memory-loss.ConclusionWe introduce CCB-diet for multi-organ dysfunction in rats, and propose its use for research on cardiovascular diseases and associated manifestations involving immense interplay of integrated pathways.
| S-EPMC4290389 | biostudies-literature
Project description:This study was conducted to evaluate the protective role of quercetin (Q) against the cytotoxicity, DNA damage and oxidative stress in rats fed aflatoxin (AFs)-contaminated diet. Female Sprague-Dawley rats were divided into six groups and treated for 21 days as follows: the control group; the group fed AFs-contaminated diet (1.4 mg/kg diet); the groups treated orally with Q at low or high dose (50 and 100 mg/kg b.w.) and the groups AFs-contaminated diet plus low or high dose of Q. At the end of experiment, blood and liver samples were collected for biochemical, histological, histochemical and genetic analyses. The results indicated that animal fed AFs-contaminated diet showed significant increase in serum biochemical parameters, oxidative stress markers and DNA fragmentation accompanied with significant decrease in total proteins, GPX, SOD, DNA and RNA content and fatty acid synthase (Fas) and TNF? gene expression in the liver tissue. Q at the two tested doses succeeded to normalize the biochemical parameters, improved the content of nucleic acids in hepatic tissues, the gene expression, the histopathological and histochemical picture of the liver. It could be concluded that Q has a potential antioxidant activity, a protective action and regulated the alteration of genes expression induced by AFs.
| S-EPMC5598466 | biostudies-literature
Project description:OBJECTIVE:Consumption of a high-fat/high-fructose Western diet (WD) is linked to rising obesity and heart disease, particularly diastolic dysfunction which characterizes early obesity/metabolic cardiomyopathy. Mounting evidence supports a role for inflammation, oxidative stress and fibrosis in the pathophysiology of metabolic cardiomyopathy. Dipeptidyl peptidase-4 (DPP-4) is a circulating exopeptidase recently reported to be elevated in the plasma of patients with insulin resistance (IR), obesity and heart failure. We hypothesized that a model of WD induced obesity/metabolic cardiomyopathy would exhibit increased DPP-4 activity and cardiac fibrosis with DPP-4 inhibition preventing cardiac fibrosis and the associated diastolic dysfunction. MATERIALS/METHODS:Four-week-old C57BL6/J mice were fed a high-fat/high-fructose WD with the DPP-4 inhibitor MK0626 for 16 weeks. Cardiac function was examined by high-resolution cine-cardiac magnetic resonance imaging (MRI). Phenotypic analysis included measurements of body and heart weight, systemic IR and DPP-4 activity. Immunohistochemistry and transmission electron microscopy (TEM) were utilized to identify underlying pathologic mechanisms. RESULTS:We found that chronic WD consumption caused obesity, IR, elevated plasma DPP-4 activity, heart enlargement and diastolic dysfunction. DPP-4 inhibition with MK0626 in WD fed mice resulted in >75% reduction in plasma DPP-4 activity, improved IR and normalized diastolic relaxation. WD consumption induced myocardial oxidant stress and fibrosis with amelioration by MK0626. TEM of hearts from WD fed mice revealed abnormal mitochondrial and perivascular ultrastructure partially corrected by MK0626. CONCLUSIONS:This study provides evidence of a role for increased DPP-4 activity in metabolic cardiomyopathy and a potential role for DPP-4 inhibition in prevention and/or correction of oxidant stress/fibrosis and associated diastolic dysfunction.
| S-EPMC4128682 | biostudies-literature
Project description:Obesity is well-known as a risk factor for heart failure, including diastolic dysfunction. However, this mechanism in high-fat diet (HFD)-induced obese rats remain controversial. The purpose of this study was to investigate whether cardiac dysfunction develops when rats are fed with a HFD for 10 weeks; additionally, we sought to investigate the association between mitochondrial abnormalities, adenosine triphosphate (ATP) levels and cardiac dysfunction.We examined myocardia in Wistar rats after 10 weeks of HFD (45 kcal% fat, n=6) or standard diet (SD, n=6). Echocardiography, histomorphologic analysis, and electron microscopy were performed. The expression levels of mitochondrial oxidative phosphorylation (OXPHOS) subunit genes, peroxisome-proliferator-activated receptor ? co-activator-1? (PGC1?) and anti-oxidant enzymes were assessed. Markers of oxidative stress damage, mitochondrial DNA copy number and myocardial ATP level were also examined.After 10 weeks, the body weight of the HFD group (349.6±22.7 g) was significantly higher than that of the SD group (286.8±14.9 g), and the perigonadal and epicardial fat weights of the HFD group were significantly higher than that of the SD group. Histomorphologic and electron microscopic images were similar between the two groups. However, in the myocardium of the HFD group, the expression levels of OXPHOS subunit NDUFB5 in complex I and PGC1?, and the mitochondrial DNA copy number were decreased and the oxidative stress damage marker 8-hydroxydeoxyguanosine was increased, accompanied by reduced ATP levels.Diastolic dysfunction was accompanied by the mitochondrial abnormality and reduced ATP levels in the myocardium of 10 weeks-HFD-induced rats.
| S-EPMC4722412 | biostudies-literature
Project description:The uterine fibrosis contributes to gestational outcomes. Collagen deposition in the uterus is related to uterine aging. Senolytic therapies are an option for reducing health complications related to aging. We investigated effects of aging and the senolytic drug combination of dasatinib plus quercetin (D+Q) on uterine fibrosis. Forty mice, 20 young females (03-months) and 20 old females (18-months), were analyzed. Young (Y) and old (O) animals were divided into groups of 10 mice, with one treatment (T) group (YT and OT) and another control © group (YC and OC). Comparative analysis of Pi3k/Akt1/mTor and p53 gene expression and related microRNAs (miR34a, miR34b, miR34c, miR146a, miR449a, miR21a, miR126a, and miR181b) among groups was performed to test effects of age and treatment on collagen deposition pathways. Aging promoted downregulation of the Pi3k/Akt1/mTor signaling pathway (P = 0.005, P = 0.031, and P = 0.028, respectively) as well as a reduction in expression of miR34c (P = 0.029), miR126a (P = 0.009), and miR181b (P = 0.007). D+Q treatment increased p53 gene expression (P = 0.041) and decreased miR34a (P = 0.016). Our results demonstrate a role for the Pi3k/Akt1/mTor signaling pathway in uterine aging and suggest for the first time a possible anti-fibrotic effect in the uterus of D+Q senolytic therapy.
| S-EPMC7041753 | biostudies-literature
Project description:Diastolic dysfunction is common in cardiovascular diseases, particularly in the case of heart failure with preserved ejection fraction. The challenge is to develop adequate animal models to envision human therapies in the future. It has been hypothesized that this diastolic dysfunction is linked to alterations in the nitric oxide (• NO) pathway. To investigate this issue further, we investigated the cardiac functions of a transgenic rat model (Tgβ3 ) that overexpresses the human β3 -adrenoceptor (hβ3 -AR) in the endothelium with the underlying rationale that the • NO pathway should be stimulated in the endothelium. Transgenic rats (Tgβ3 ) that express hβ3 -AR under the control of intercellular adhesion molecule 2 promoter were developed for a specific expression in endothelial cells. Transcriptomic analyses were performed on left ventricular tissue from 45-week-old rats. Among all altered genes, we focus on • NO synthase expression and endothelial function with arterial reactivity and evaluation of • NO and O2•- production. Cardiac function was characterized by echocardiography, invasive haemodynamic studies, and working heart studies. Transcriptome analyses illustrate that several key genes are regulated by the hβ3 -AR overexpression. Overexpression of hβ3 -AR leads to a reduction of Nos3 mRNA expression (-72%; P < 0.05) associated with a decrease in protein expression (-19%; P < 0.05). Concentration-dependent vasodilation to isoproterenol was significantly reduced in Tgβ3 aorta (-10%; P < 0.05), while • NO and O2•- production was increased. In the same time, Tgβ3 rats display progressively increasing diastolic dysfunction with age, as shown by an increase in the E/A filing ratio [1.15 ± 0.01 (wild type, WT) vs. 1.33 ± 0.04 (Tgβ3 ); P < 0.05] and in left ventricular end-diastolic pressure [5.57 ± 1.23 mmHg (WT) vs. 11.68 ± 1.11 mmHg (Tgβ3 ); P < 0.05]. In isolated working hearts, diastolic stress using increasing preload levels led to a 20% decrease in aortic flow [55.4 ± 1.9 mL/min (WT) vs. 45.8 ± 2.5 mL/min (Tgβ3 ); P < 0.05]. The Tgβ3 rat model displays the expected increase in • NO production upon ageing and develops diastolic dysfunction. These findings provide a further link between endothelial and cardiac dysfunction. This rat model should be valuable for future preclinical evaluation of candidate drugs aimed at correcting diastolic dysfunction.
| S-EPMC7754894 | biostudies-literature
Project description:Cholesterol is essential for cells to grow and proliferate. Normal mammalian cells meet their need for cholesterol through its uptake or de novo synthesis1, but the extent to which cancer cells rely on each of these pathways remains poorly understood. Here, using a competitive proliferation assay on a pooled collection of DNA-barcoded cell lines, we identify a subset of cancer cells that is auxotrophic for cholesterol and thus highly dependent on its uptake. Through metabolic gene expression analysis, we pinpoint the loss of squalene monooxygenase expression as a cause of cholesterol auxotrophy, particularly in ALK+ anaplastic large cell lymphoma (ALCL) cell lines and primary tumours. Squalene monooxygenase catalyses the oxidation of squalene to 2,3-oxidosqualene in the cholesterol synthesis pathway and its loss results in accumulation of the upstream metabolite squalene, which is normally undetectable. In ALK+ ALCLs, squalene alters the cellular lipid profile and protects cancer cells from ferroptotic cell death, providing a growth advantage under conditions of oxidative stress and in tumour xenografts. Finally, a CRISPR-based genetic screen identified cholesterol uptake by the low-density lipoprotein receptor as essential for the growth of ALCL cells in culture and as patient-derived xenografts. This work reveals that the cholesterol auxotrophy of ALCLs is a targetable liability and, more broadly, that systematic approaches can be used to identify nutrient dependencies unique to individual cancer types.
| S-EPMC6405297 | biostudies-literature
Project description:Key pointsThe results of the present study establish the temporal pattern of age-related vascular dysfunction across the adult lifespan in sedentary mice consuming a non-Western diet, and the underlying mechanisms The results demonstrate that consuming a Western diet accelerates and exacerbates vascular ageing across the lifespan in sedentary mice They also show that lifelong voluntary aerobic exercise has remarkable protective effects on vascular function throughout the lifespan, in the setting of ageing alone, as well as ageing compounded by Western diet consumption Overall, the results indicate that amelioration of mitochondrial oxidative stress and inflammation are key mechanisms underlying the voluntary aerobic exercise-associated preservation of vascular function across the lifespan in both the presence and absence of a Western dietary pattern ABSTRACT: Advancing age is the major risk factor for cardiovascular diseases, driven largely by vascular endothelial dysfunction (impaired endothelium-dependent dilatation, EDD) and aortic stiffening (increased aortic pulse wave velocity, aPWV). In humans, vascular ageing occurs in the presence of differences in diet and physical activity, but the interactive effects of these factors are unknown. We assessed carotid artery EDD and aPWV across the lifespan in mice consuming standard (normal) low-fat chow (NC) or a high-fat/high-sucrose Western diet (WD) in the absence (sedentary, SED) or presence (voluntary wheel running, VWR) of aerobic exercise. Ageing impaired nitric oxide-mediated EDD (peak EDD 88 ± 12% 6 months P = 0.003 vs. 59 ± 9% 27 months NC-SED), which was accelerated by WD (60 ± 18% 6 months WD-SED). In NC mice, aPWV increased 32% with age (423 ± 13 cm/s at 24 months P < 0.001 vs. 321 ± 12 cm/s at 6 months) and absolute values were an additional ∼10% higher at any age in WD mice (P = 0.042 vs. NC-SED). Increases in aPWV with age in NC and WD mice were associated with 30-65% increases in aortic intrinsic wall stiffness (6 vs. 19-27 months, P = 0.007). Lifelong aerobic exercise prevented age- and WD-related vascular dysfunction across the lifespan, and this protection appeared to be mediated by mitigation of vascular mitochondrial oxidative stress and inflammation. Our results depict the temporal impairment of vascular function over the lifespan in mice, acceleration and exacerbation of that dysfunction with WD consumption, the remarkable protective effects of voluntary aerobic exercise, and the underlying mechanisms.
| S-EPMC7856030 | biostudies-literature