Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental evidences suggest an implication of the renin angiotensin system (RAS) as a potential determinant of cognitive functions. To explore this hypothesis, we compared the distribution of an insertion (I)/deletion (D) polymorphism of the gene coding for the angiotensin I converting enzyme (ACE), a key enzyme of the RAS, in 228 elderly with cognitive impairment to that of 255 controls. The ACE D allele frequency was higher in the group with cognitive impairment (0.594) than in controls (0.514) (P < 0.02). The ACE DD genotype carriers had an increased risk of cognitive impairment (OR = 1.60, 95% CI (1.04-2.36), P < 0.03), independent of other risk factors of cognitive impairment: age, gender and presence of the apolipoprotein E epsilon 4 allele. This association was stronger in men (OR = 3.25, 95% CI (1.40-7.58), P < 0.006). This result suggests a possible implication of the RAS in human brain and cognitive functions.
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PMID:The deletion allele of the angiotensin I converting enzyme gene as a genetic susceptibility factor for cognitive impairment. 891 8

Recent reports sustain the hypothesis of tight links between vascular and neurodegenerative diseases: associations between atherosclerosis lesions and Alzheimer's disease (AD), increased risk of AD for hypertensive subjects, decreased risk of dementia for elderly treated with hypotensive drugs, and a major impact of apolipoprotein E polymorphism, a protein of the lipid metabolism, on the occurrence of AD. All these results suggest that vascular determinants, both environmental and genetic, may predispose to or speed up dementia. As a major player of vascular homeostasis, the renin angiotensin system (RAS) proteins constitute an interesting source of candidate genes. Among these, the angiotensin I-converting enzyme gene (ACE), a central enzyme of the RAS, presents in its sequence a deletion (D)/insertion (I) polymorphism associated with variations of plasma ACE levels and with the risk of myocardial infarction. We explored the impact of this genetic polymorphism on the risk of cognitive impairment and of dementia in several epidemiological studies. Physiopathological hypotheses suggest a possible involvement of the RAS proteins in the occurrence and evolution of AD. Moreover, although inconsistent, several results of case-control studies tend to suggest that the ACE I/D genetic polymorphism may constitute a genetic susceptibility factor for dementia, reinforcing the hypothesis of a major implication of vascular risk factors in the occurrence of dementia.
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PMID:The renin angiotensin system and Alzheimer's disease. 1081 34

Alzheimer's disease is a primary degenerative dementia and is not considered to be of vascular origin. Furthermore, severe cerebrovascular diseases are generally exclusionary for the clinical diagnosis. During recent years both epidemiological and neuropathological studies have suggested an association between Alzheimer's disease and several vascular risk factors, such as hypertension, inheritance of the apolipoprotein E epsilon4 allele, coronary heart disease, diabetes mellitus, ischaemic white matter lesions and generalised atherosclerosis. These findings may reflect an overdiagnosis of Alzheimer's disease in individuals with silent cerebrovascular disease or that cerebrovascular disease may affects the clinical expression of Alzheimer's disease. Further possibilities include that Alzheimer's disease may increase the risk of vascular disease or that vascular disease may stimulate the Alzheimer's disease process. Similar mechanisms may also be involved in the pathogenesis of both disorders, such as disturbances in the renin-angiotensin system, apoptosis, and psychological stress.
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PMID:Vascular aspects in Alzheimer's disease. 1096 16

Despite considerable evidence suggesting that hypertension contributes to the development and progression of atherosclerosis, the causative links remain unclear. We have tested the effects of chronic hypertension induced by suprarenal aortic constriction on the development of atherosclerosis in apolipoprotein E-deficient (Apoe-/-) mice. Compared with a sham operation, narrowing the aortic luminal diameter by 33% increased blood pressure proximal to the constriction by approximately 15 mm Hg, but the pressures distal to the constriction were unchanged. Kidney renin mRNA and plasma renin activity were also unaffected. Compared with plaque size after the sham operation, atherosclerotic plaque size in the aortic root 8 weeks after coarctation was increased to 245% and 152% in males and females, respectively. Aortic segments at the constriction were free of atherosclerotic deposits, but segments proximal to the constriction were dilated and had atherosclerotic lesions. Thrombi were present immediately below the constriction in Apoe-/- and wild-type vessels. Surprisingly, compared with wild-type mice, the Apoe-/- mice were more susceptible to the cardiac hypertrophy and dysfunction induced by pressure overload. Thus, aortic coarctation exacerbates atherosclerosis in vessels proximal to the constriction without a concomitant increase in the renin-angiotensin system. Our study also suggests that apolipoprotein E plays an important role in modulating cardiac hypertrophy.
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PMID:Aortic constriction exacerbates atherosclerosis and induces cardiac dysfunction in mice lacking apolipoprotein E. 1188 92

Epidemiological studies from the last decade have begun to produce evidence that the perceived joint occurrence of vascular disease and Alzheimer's disease (AD), both common elderly disorders more often believed to occur by chance due to their high prevalence, may now actually have a more pathological significance. The following review discusses some of this evidence and the implications for cognitive decline and the development of AD and how a well-known cardiovascular risk factor gene, the apolipoprotein E (APOE) gene, plays a significant role in the molecular genetics of AD. It also introduces and discusses recent and compelling evidence for the involvement of another well-known cardiovascular risk factor gene, the angiotensin-converting enzyme (ACE1) gene, in the pathogenesis of AD. This role is suggested in terms of recent molecular genetic association evidence implicating the ACE1 insertion/deletion (indel) polymorphism, a more recent large haplotype study that greatly extends the ACE1 indel evidence and incorporates knowledge accrued from previous cardiovascular disease-focused ACE1 haplotype studies. Finally, this paper discusses very recent biological evidence that further supports a role for ACE1 and hypothesises a number of readily testable mechanisms by which the ACE1 enzyme and other components of the renin-angiotensin-aldosterone system may be implicated in increased risk and/or the progression of AD.
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PMID:The renin-angiotensin-aldosterone system and Alzheimer s disease? 1280 89

We recently described that a treatment with the angiotensin AT1 receptor antagonist irbesartan inhibits atherosclerotic lesion development, macrophage accumulation, and monocyte chemoattractant protein-1 (MCP-1) as well as the chemokine KC expression in apolipoprotein E-deficient (apoE-deficient) mice. The present study addresses whether these and other chemokines are expressed not only during the initiation but also during the development of atherosclerotic lesions and whether irbesartan can inhibit the expression of these chemokines during lesion progression. The time course of lesion development was assessed in apoE-deficient mice aged 1 to 9 months and the relative expression of chemokines was quantified by RT-PCR. Significant lesion formation already appeared in 3-month-old apoE-deficient mice, and progressed further to the age of 9 months. The expression of MCP-1 and KC (the mouse homologue of Groalpha), was induced at 1 month in apoE-deficient as compared with wild type (C57/Bl6) mice, and was observed before any detectable histologic changes. MCP-1 and KC expression remained high during lesion progression. The expression of macrophage inflammatory protein-2 (MIP-2, the mouse Grobeta/gamma homologue) and macrophage inflammatory protein-1alpha (MIP-1alpha) was increased in lesions from 4-month-old mice onward, whereas Regulated upon Activation of Normal T-cells Expressed and Secreted (RANTES) was significantly induced in 6- to 9-month-old mice only. Irbesartan (50 mg/kg/d) administered from the age of 3 months onward significantly reduced the progression of the lesions as well as the expression of the chemokines. A short-term treatment with irbesartan significantly inhibited the expression of MCP-1 and KC, suggesting that activation of the renin-angiotensin system is involved in up-regulation of these chemokines and that this effect represents a potential mechanism by which irbesartan inhibits plaque development and progression.
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PMID:Lesion progression in apoE-deficient mice: implication of chemokines and effect of the AT1 angiotensin II receptor antagonist irbesartan. 1471 5

In humans, the incidence and severity of abdominal aortic aneurysms (AAA) are greater in males than in females. Chronic infusion of angiotensin II (AngII) into apolipoprotein E-deficient (apoE(-/-)) mice promotes atherosclerosis and causes the formation of AAAs. Just as human males are more susceptible to developing AAAs, male mice are more susceptible to AngII-induced AAAs. We hypothesized that sex steroid hormones mediate gender differences in AngII-induced AAA through regulation of the renin-angiotensin system. To define the role of ovarian hormones, female apoE(-/-) mice were subjected to ovariectomy or sham operation and infused with AngII (1000 ng/kg x min) for 28 d. Ovariectomy had no effect on AngII-induced atherosclerosis, nor did it influence the incidence or severity of AAA. To define the role of testicular hormones, male apoE(-/-) mice were subjected to orchidectomy (orx) or sham operation and infused with AngII (1000 ng/kg x min) for 28 d. Orx resulted in a profound reduction in AAA incidence (85% vs. 18%, sham vs. orx; P = 0.003) to the level observed in females (25%). However, orx had no effect on AngII-induced reductions in plasma renin concentration or spleen AngII receptor density. In contrast, orx resulted in an increase in atherosclerosis (0.46 +/- 0.07 vs. 1.20 +/- 0.21 mm(2), sham vs. orx; P = 0.002). These results suggest that estrogen does not mediate gender differences in AngII-induced AAA. In contrast, androgens mediate a higher incidence of AngII- induced AAA, through mechanisms that do not appear to involve circulating renin or angiotensin receptor density.
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PMID:Orchidectomy, but not ovariectomy, regulates angiotensin II-induced vascular diseases in apolipoprotein E-deficient mice. 1510 80

Angiotensin (Ang) II infusion increases atherosclerosis and leads to the formation of abdominal aortic aneurysms in apolipoprotein E-deficient (ApoE-/-) mice. Conversely, blockade of the renin-angiotensin system (RAS) decreases atherosclerosis in this model. However, there are conflicting data in the literature concerning responses to both Ang II infusion and RAS blockade which may depend on age, sex, dose, duration of treatment, and the site at which lesion area was measured. In the present study we examined the effects of Ang II infusion on lesion formation in male ApoE-/- mice both at the aortic sinus and in the descending aorta, starting at different ages, and varying in duration. We also tested the effects of the Ang II receptor antagonist losartan at different doses in both males and females. Blood pressure and plasma renin concentration (PRC) were measured as indicators of the hemodynamic and neurohormonal effects of these treatments. Administration of Ang II increased lesion area much more in the descending aorta than at the aortic sinus. However, spontaneous lesion development at the aortic sinus was much greater than in more distal regions of the aorta. Aneurysms were observed in all treatment groups but were less severe in animals treated from 4 weeks age, possibly because of protective remodeling. Losartan treatment reduced lesion area at the aortic sinus, although differences were only significant in female mice. These findings demonstrate regional and temporal differences in the sensitivity of the aorta to the effects of RAS stimulation and blockade, and may help to explain some of the discrepancies between previous reports from other laboratories.
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PMID:Differential effects of angiotensin II on atherogenesis at the aortic sinus and descending aorta of apolipoprotein-E-deficient mice. 1583 57

While diabetes mellitus is most often associated with hypertension, dyslipidemia, and obesity, these factors do not fully account for the increased burden of cardiovascular disease in patients with the disease. This strengthens the need for comprehensive studies investigating the underlying mechanisms mediating diabetic cardiovascular disease and, more specifically, diabetes-associated atherosclerosis. In addition to the recognized metabolic abnormalities associated with diabetes mellitus, upregulation of putative pathological pathways such as advanced glycation end products, the renin-angiotensin system, oxidative stress, and increased expression of growth factors and cytokines have been shown to play a causal role in atherosclerotic plaque formation and may explain the increased risk of macrovascular complications. This review discusses the methods used to assess the development of atherosclerosis in the clinic as well as addressing novel biomarkers of atherosclerosis, such as low-density lipoprotein receptor-1. Experimental models of diabetes-associated atherosclerosis are discussed, such as the streptozocin-induced diabetic apolipoprotein E knockout mouse. Results of major clinical trials with inhibitors of putative atherosclerotic pathways are presented. Other topics covered include the role of HMG-CoA reductase inhibitors and fibric acid derivatives with respect to their lipid-altering ability, as well as their emerging pleiotropic anti-atherogenic actions; the effect of inhibiting the renin-angiotensin system by either ACE inhibition or angiotensin II receptor antagonism; the effect of glycemic control and, in particular, the promising role of thiazolidinediones with respect to their direct anti-atherogenic actions; and newly emerging mediators of diabetes-associated atherosclerosis, such as advanced glycation end products, vascular endothelial growth factor and platelet-derived growth factor. Overall, this review aims to highlight the observation that various pathways, both independently and in concert, appear to contribute toward the pathology of diabetes-associated atherosclerosis. Furthermore, it reflects the need for combination therapy to combat this disease.
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PMID:Diabetes mellitus-associated atherosclerosis: mechanisms involved and potential for pharmacological invention. 1648 46

The incidence of diabetes is increasing at an alarming rate to the point where it is becoming an epidemic. An ageing population, sedentary lifestyle and an unhealthy diet are considered to have contributed toward this. What we must now consider is not only the burden of the disease but the complications that arise from diabetes, in particular kidney and heart disease. Foremost, more than half of the diabetic population will die from cardiovascular-related causes. Whilst diabetes is most often associated with hypertension, dyslipidaemia and obesity, these factors do not fully account for the increased burden of cardiovascular disease in people with diabetes. This strengthens the need for comprehensive studies investigating the underlying mechanisms mediating diabetic cardiovascular disease, and more specifically, diabetes-associated atherosclerosis. In addition to the recognised metabolic abnormalities associated with diabetes, upregulation of putative pathological pathways such as advanced glycation endproducts, renin-angiotensin system, oxidative stress and increased expression of growth factors and cytokines have been observed in the setting of diabetes. All of these have been shown to play a causal role in atherosclerotic plaque formation and thus may explain the increased risk of macrovascular complications in those patients with diabetes. In this review the effect of inhibiting the renin-angiotensin system with angiotensin converting enzyme inhibition and a comparison to angiotensin II receptor antagonism is discussed, with the results of clinical trails reflecting the more recently discovered, non-haemodynamic, proatherogenic actions of angiotensin II. The need for experimental models of diabetes-associated atherosclerosis will be covered, with particular emphasis given to the streptozotocin-diabetic apolipoprotein E knockout mouse. Finally, growth factors, including vascular endothelial growth factor and platelet-derived growth factor are discussed in detail.
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PMID:Preventing atherosclerosis with angiotensin-converting enzyme inhibitors: emphasis on diabetic atherosclerosis. 1650 70


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