Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory processes play an important role in the pathogenesis of vascular diseases, and insulin-resistant diabetes mellitus type 2 represents an important risk factor for the development of atherosclerosis. To directly address the role of insulin resistance in myeloid lineage cells in the development of atherosclerosis, we have created mice with myeloid lineage-specific inactivation of the insulin receptor gene. On an ApoE-deficient background, MphIRKO mice developed smaller atherosclerotic lesions. There was a dramatic decrease in LPS-stimulated IL-6 and IL-1beta expression in the presence of macrophage autonomous insulin resistance. Consistently, while insulin-resistant IRS-2-deficient mice on an ApoE-deficient background display aggravated atherosclerosis, fetal liver cell transplantation of IRS-2(-/-) ApoE(-/-) cells ameliorated atherosclerosis in Apo-E-deficient mice. Thus, systemic versus myeloid cell-restricted insulin resistance has opposing effects on the development of atherosclerosis, providing direct evidence that myeloid lineage autonomous insulin signaling provides proinflammatory signals predisposing to the development of atherosclerosis.
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PMID:Myeloid lineage cell-restricted insulin resistance protects apolipoproteinE-deficient mice against atherosclerosis. 1658 Oct 2

Insulin resistance in diabetes and metabolic syndrome is thought to increase susceptibility to atherosclerotic cardiovascular disease, but the underlying mechanisms are poorly understood. To evaluate the possibility that decreased insulin signaling in macrophage foam cells might worsen atherosclerosis, Ldlr(-/-) mice were transplanted with insulin receptor Insr(+/+) or Insr(-/-) bone marrow. Western diet-fed Insr(-/-) recipients developed larger, more complex lesions with increased necrotic cores and increased numbers of apoptotic cells. Insr(-/-) macrophages showed diminished Akt phosphorylation and an augmented ER stress response, leading to induction of scavenger receptor A and increased apoptosis when challenged with cholesterol loading or nutrient deprivation. These studies suggest that defective insulin signaling and reduced Akt activity impair the ability of macrophages to deal with ER stress-induced apoptosis within atherosclerotic plaques.
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PMID:Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. 1658 Oct 3

Recent studies suggest that adipose tissue hormones ("adipokines") are involved in the pathogenesis of various complications of obesity, including hyperlipidemia, diabetes mellitus, arterial hypertension, atherosclerosis, and heart failure. Apelin and visfatin are two recently described adipokines, although they are also synthesized outside adipose tissue. Apelin exists in at least three forms, consisting of 13, 17, or 36 amino acids, all originating from a common 77-amino-acid precursor. In the cardiovascular system, apelin elicits endothelium-dependent, nitric oxide-mediated vasorelaxation and reduces arterial blood pressure. In addition, apelin demonstrates potent and long-lasting positive inotropic activity which is preserved even in injured myocardium and is not accompanied by myocardial hypertrophy. Apelin synthesis in adipocytes is stimulated by insulin, and plasma apelin level markedly increases in obesity associated with insulin resistance and hyperinsulinemia. In addition to regulating cardiovascular function, apelin inhibits water intake and vasopressin production. Visfatin, previously recognized as a pre-B cell colony-enhancing factor (PBEF), is abundantly expressed in visceral adipose tissue and is upregulated in some, but not all, animal models of obesity. Preliminary studies suggest that plasma visfatin concentration is also increased in humans with abdominal obesity and/or type 2 diabetes mellitus. Visfatin binds to the insulin receptor at a site distinct from insulin and exerts hypoglycemic effect by reducing glucose release from hepatocytes and stimulating glucose utilization in peripheral tissues. Thus, apelin and visfatin are unique among adipose tissue hormones in that they are upregulated in the obese state and both exert primarily beneficial effects.
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PMID:Apelin and visfatin: unique "beneficial" adipokines upregulated in obesity? 1694 Sep 39

The renin-angiotensin system is a central component of the physiological and pathological responses of cardiovascular system. Its primary effector hormone, angiotensin II (ANG II), not only mediates immediate physiological effects of vasoconstriction and blood pressure regulation, but is also implicated in inflammation, endothelial dysfunction, atherosclerosis, hypertension, and congestive heart failure. The myriad effects of ANG II depend on time (acute vs. chronic) and on the cells/tissues upon which it acts. In addition to inducing G protein- and non-G protein-related signaling pathways, ANG II, via AT(1) receptors, carries out its functions via MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases [PDGF, EGFR, insulin receptor], and nonreceptor tyrosine kinases [Src, JAK/STAT, focal adhesion kinase (FAK)]. AT(1)R-mediated NAD(P)H oxidase activation leads to generation of reactive oxygen species, widely implicated in vascular inflammation and fibrosis. ANG II also promotes the association of scaffolding proteins, such as paxillin, talin, and p130Cas, leading to focal adhesion and extracellular matrix formation. These signaling cascades lead to contraction, smooth muscle cell growth, hypertrophy, and cell migration, events that contribute to normal vascular function, and to disease progression. This review focuses on the structure and function of AT(1) receptors and the major signaling mechanisms by which angiotensin influences cardiovascular physiology and pathology.
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PMID:Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. 1687 Aug 27

Insulin resistance (IR) is the underlying defect in >90% of patients with type 2 diabetes mellitus and the major pathologic mechanism for the associated susceptibility to premature cardiovascular disease (CVD). The progression of IR to diabetes parallels the progression of endothelial dysfunction to atherosclerosis. The downregulation of the antiatherogenic phosphatidylinositol-3-kinase-mediated insulin receptor-signaling pathway, and maintained activity of the proatherogenic mitogenic-activated protein kinase pathway in insulin-resistant states, leads to accelerated atherosclerosis. Efforts to prevent or slow the epidemic of atherothrombotic CVD must focus on the reversal of the disturbances in glucose and lipid homeostasis through the amelioration of IR.
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PMID:Role of insulin resistance and hyperglycemia in the development of atherosclerosis. 1730 54

Insulin resistance is well established as an independent risk factor for the development of type 2 diabetes and cardiovascular atherosclerosis. Most studies have examined atherogenesis in models of severe insulin resistance or diabetes. However, by the time of diagnosis, individuals with type 2 diabetes already demonstrate a significant atheroma burden. Furthermore, recent studies suggest that, even in adolescence, insulin resistance is a progressive disorder that increases cardiovascular risk. In the present report, we studied early mechanisms of reduction in the bioavailability of the antiatheroscerotic molecule nitric oxide (NO) in very mild insulin resistance. Mice with haploinsufficiency for the insulin receptor (IRKO) are a model of mild insulin resistance with preserved glycemic control. We previously demonstrated that 2-mo-old (Young) IRKO mice have preserved vasorelaxation responses to ACh. This remained the case at 4 mo of age. However, by 6 mo, despite no significant deterioration in glucose homeostasis (Adult), IRKO mice had marked blunting of ACh-mediated vasorelaxation [IRKO maximum contraction response (E(max)) 66 +/- 5% vs. wild type 87 +/- 4%, P < 0.01]. Despite the endothelial dysfunction demonstrated, aortic endothelial nitric oxide synthase (eNOS) mRNA levels were similar in Adult IRKO and wild-type mice, and, interestingly, aortic eNOS protein levels were increased, suggesting a compensatory upregulation in the IRKO. We then examined the potential role of reactive oxygen species in mediating early endothelial dysfunction. The superoxide dismutase mimetic Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP) restored ACh relaxation responses in the Adult IRKO (E(max) to ACh with MnTMPyP 85 +/- 5%). Dihydroethidium fluorescence of aortas and isolated coronary microvascular endothelial cells confirmed a substantial increase in endothelium-derived reactive oxygen species in IRKO mice. These data demonstrate that mild insulin resistance is a potent substrate for accelerated endothelial dysfunction and support a role for endothelial cell superoxide production as a mechanism underlying the early reduction in NO bioavailability.
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PMID:Accelerated endothelial dysfunction in mild prediabetic insulin resistance: the early role of reactive oxygen species. 1771 85

Statin-treatment of fructose-fed/insulin resistant hamsters was recently shown to ameliorate metabolic dyslipidemia and hepatic VLDL overproduction. Here, we provide evidence that rosuvastatin treatment of insulin resistant hamsters can induce improvements in hepatic and whole body insulin sensitivity. Treatment with 10 mg/kg/day rosuvastatin for 10 days significantly reduced fasting insulin (-59%) and triglyceride (-50%) levels in fructose-fed hamsters (p<0.05). Following an intraperitoneal (IP) glucose challenge, rosuvastatin-treated hamsters exhibited enhanced glucose clearance compared to untreated hamsters maintained on the high-fructose diet (area under curve (AUC)=1772+/-223 mM min vs. 2413+/-253 mM min, respectively; p<0.002) with a significant reduction in 2h post-challenge glucose (n=5, p<0.02). Rosuvastatin-treatment also significantly improved sensitivity to an IP insulin challenge (AUC=314+/-39 mM min vs. 195+/-22 mM min for rosuvastatin-treated and fructose-fed hamsters, respectively; p<0.04, n=3). At the molecular level, significant increases in tyrosine-phosphorylation of the hepatic insulin receptor and IRS-1 were observed for rosuvastatin-treated hamsters (+37% and +58%, respectively) compared to fructose-fed controls following an intravenous (IV) bolus of insulin (p<0.05). Increases in insulin receptor and IRS-1 phosphorylation were also observed in muscle and adipose tissue. Analysis of hepatic Akt phosphorylation and mass revealed a small (25%) increase in serine phosphorylation of Akt with no significant change in Akt mass, although serine-phosphorylation and mass of Akt2 were significantly increased (+32%, p=0.03, and +42%, p=0.01, respectively). Interestingly, expression of PTP-1B, a key negative regulator of insulin signaling, showed a non-significant trend toward reduction in liver and was significantly reduced in adipose tissue (-20% and -37%, respectively). Taken together, these data suggest that statin-treatment increases whole body and peripheral tissue insulin sensitivity via improved cellular insulin signal transduction.
Atherosclerosis 2008 May
PMID:Effect of rosuvastatin on insulin sensitivity in an animal model of insulin resistance: evidence for statin-induced hepatic insulin sensitization. 1809 97

Insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial. Liver insulin receptor knockout (LIRKO) mice have pure hepatic insulin resistance. On a standard chow diet, LIRKO mice have a proatherogenic lipoprotein profile with reduced high-density lipoprotein (HDL) cholesterol and very low-density lipoprotein (VLDL) particles that are markedly enriched in cholesterol. This is due to increased secretion and decreased clearance of apolipoprotein B-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of Pgc-1 beta (Ppargc-1b), which promotes VLDL secretion, but decreased expression of Srebp-1c (Srebf1), Srebp-2 (Srebf2), and their targets, the lipogenic enzymes and the LDL receptor. Within 12 weeks on an atherogenic diet, LIRKO mice show marked hypercholesterolemia, and 100% of LIRKO mice, but 0% of controls, develop severe atherosclerosis. Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome.
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PMID:Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. 1824 66

Recent studies have shown that insulin and insulin-like growth factor (IGF)-1 signaling are involved in the control of ageing and longevity in model organisms. Based on these studies, genes involved in the insulin/IGF-1 signaling pathway are believed to play a role in longevity throughout evolution and could also be important in determining human longevity. However, human studies have yielded conflicting and controversial results. In human, defects in insulin receptor signaling cause insulin resistance and diabetes, and IGF-1 deficiency is associated with an increased risk of cardiovascular disease and atherosclerosis. Interestingly, insulin sensitivity normally decreases during aging; however, centenarians were reported to maintain greatly increased insulin sensitivity and had a lower prevalence of the metabolic syndrome as compared to younger subjects. Additionally, a longitudinal study revealed that insulin-sensitizing hormones, including leptin and adiponectin, were significantly associated with the survival of centenarians, indicating that an efficient insulin response may influence human longevity.
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PMID:The metabolic syndrome, IGF-1, and insulin action. 1867 19

Studies over the last several years have revealed important roles of the body fat content, caloric intake and nutrition, insulin/IGF-1 signaling systems, and pathways involved in oxidative stress and control of protein acetylation on life span. Although the discovery of longevity genes supports the concept that life span is genetically determined, adipose tissue seems to be a pivotal organ in the aging process and in the determination of life span. Leanness and caloric restriction have been shown to increase longevity in organisms ranging from yeast to mammals. Increased longevity in mice with a fat-specific disruption of the insulin receptor gene (FIRKO) suggests that reduced adiposity, even in the presence of normal or increased food intake, leads to an extended life span. Reduced fat mass has an impact on longevity in a number of other model organisms. In Drosophila, a specific reduction in the fat body through overexpression of forkhead type transcription factor (dFOXO) extends life span. Sirtuin 1 (SIRT1), the mammalian ortholog of the life-extending yeast gene silent information regulator 2 (SIR2), was proposed to be involved in the molecular mechanisms linking life span to adipose tissue. Moreover, in the control of human aging and longevity, one of the striking physiological characteristics identified in centenarians is their greatly increased insulin sensitivity even compared with younger individuals. On the other hand, overweight and obesity seem to be associated with decreased life span in humans. In addition, it was recently shown that modifiable risk factors during the later years of life, including smoking, obesity, and hypertension, are associated not only with lower life expectancy, but also with poor health and function during older age. There is growing evidence that the effect of reduced adipose tissue mass on life span could be due to the prevention of obesity-related metabolic disorders including type 2 diabetes and atherosclerosis.
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PMID:Fat tissue and long life. 2005 78


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