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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review introduces recent progress in molecular genetics of cardiovascular diseases. Many genes and their mutations causing familial cardiovascular diseases have been discovered, including familial hypertrophic cardiomyopathy which is caused by mutated cardiac beta myosin heavy chain, light chains, troponin T, troponin I, or alpha-tropomyosin, and long QT syndrome by KvLQT1, HERG, minK or cardiac voltage-dependent Na channel mutation. The mutations in causative genes can affect clinical courses of diseases; amino acid substitutions of cardiac beta myosin heavy chain with charge changes seem to cause poorer prognosis of hypertrophic cardiomyopathy. Besides monogenic diseases, there are many cardiovascular diseases affected with genetic polymorphisms, such as hypertension, ischemic heart disease and atherosclerosis. Specific amino acid mutations or polymorphisms in the promoter region of the genes are known to become a risk factor of these diseases. Polymorphisms of genes encoding apolipoprotein E, angiotensin converting enzyme, angiotensinogen and endothelial NO synthase (ecNOS) have been well characterized as an important risk factor of cardiovascular diseases. We recently found a novel gene which seems to affect human aging phenotype and vascular endothelial function. It is important as a future study to clarify the regulatory mechanisms of the klotho gene in the cardiovascular system and the clinical significance of klotho gene polymorphisms.
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PMID:[Molecular genetics of cardiovascular diseases]. 956 64

We recently reported the isolation of the klotho gene, which in predominantly expressed in the kidney and involved in human aging phenotypes. In our previous studies, we demonstrated that the Klotho protein or its metabolites may possibly function as humoral factor(s) and protect against endothelial dysfunction because acetylcholine-mediated NO production in arteries was impaired in heterozygous klotho deficient mice (kl/+). However, the pathophysiological significance of the Klotho protein has not been clarified yet. In the present study, we examined expression of the klotho gene in the kidney of the following rat models for human diseases: (1) spontaneously hypertensive rat, (2) deoxycorticosterone acetate-salt hypertensive rat, (3) 5/6 nephrectomized rat, (4) non-insulin-dependent diabetes mellitus rat (the Otsuka Long-Evans Tokushima Fatty rat), and (5) rat with acute myocardial infarction. The expression levels of klotho mRNA in the kidney in these models were significantly lower than controls except for MI rats. This is the first report showing the expression of the klotho gene in the kidney is regulated under sustained circulatory stress such as long-term hypertension, diabetes mellitus, and chronic renal failure.
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PMID:Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats. 973 Dec 28

The human aging process is associated with vascular endothelial dysfunction. However, humoral factors which might protect against endothelial dysfunction during aging have not yet been identified. We recently identified the klotho gene as a possible regulator of human aging. In the present study using the klotho-deficient heterozygous mouse, we examined whether the Klotho protein is a humoral factor protecting against endothelial dysfunction. We further cloned rat klotho cDNA and investigated whether klotho mRNA expression in rat kidney is altered under pathological conditions such as hypertension, hyperlipidemia, renal failure, and inflammatory stress. The Klotho protein itself, or its metabolites, promotes endothelial NO production in aorta as well as arterioles, and klotho mRNA in kidney is downregulated under sustained circulatory stress.
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PMID:Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases. 1089 40

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses multiple aging phenotypes (e.g., arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, and short life span). We have previously shown that mice heterozygous for a defect in the klotho gene upon parabiosis with wild-type mice show improved endothelial function, suggesting that the klotho gene product protects against endothelial dysfunction. In the present study, using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat which demonstrates multiple atherogenic risk factors (e.g., hypertension, obesity, severe hyperglycemia, and hypertriglyceridemia) and is thus considered an experimental animal model of atherosclerotic disease, we show that adenovirus-mediated klotho gene delivery can (1) ameliorate vascular endothelial dysfunction, (2) increase nitric oxide production, (3) reduce elevated blood pressure, and (4) prevent medial hypertrophy and perivascular fibrosis. Based on these findings, klotho gene delivery improves endothelial dysfunction through a pathway involving nitric oxide, and is involved in modulating vascular function (e.g., hypertension and vascular remodeling). Our findings establish the basis for the therapeutic potential of klotho gene delivery in atherosclerotic disease.
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PMID:In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome. 1102 45

Targeted disruption of the klotho gene induces multiple phenotypes characteristic of human aging, including arteriosclerosis, pulmonary emphysema and osteoporosis. Moreover, we previously observed that insufficient klotho expression in mice leads to endothelial dysfunction. In the present study, we used Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which exhibit hypertension, obesity, severe hyperglycemia and hypertriglyceridemia, and are thus considered an animal model of atherogenic disease, to test the effects of oral administration of troglitazone (200 mg/kg) on renal klotho mRNA expression and endothelial function. Systolic blood pressure, body weight, plasma glucose and triglyceride levels were all significantly higher in 30-week-old OLETF rats than in controls (LETO; Long-Evans Tokushima Otsuka) (p<0.05, n=7). In addition, endothelium-dependent relaxation of the aorta in response to 10(-5) M acetylcholine was significantly attenuated in OLETF rats (p<0.05, n=7), as was renal expression of klotho mRNA. Administration of troglitazone for 10 weeks significantly reduced systolic blood pressure, plasma glucose and triglyceride levels in OLETF rats, while augmenting endothelium-dependent aortic relaxation and renal klotho mRNA expression. These findings suggest that troglitazone protects the vascular endothelium against damage caused by the presence of multiple atherogenic factors.
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PMID:Troglitazone improves endothelial function and augments renal klotho mRNA expression in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with multiple atherogenic risk factors. 1176 31

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses the expression of multiple aging-associated phenotypes. This gene is predominantly expressed in the kidney. Recent studies have shown that expression of renal klotho gene is regulated in animal models of metabolic diseases and in humans with chronic renal failure. However, little is known about the mechanisms and the physiological relevance of the regulation of the expression of the klotho gene in the kidney in some diseased conditions. In the present study, we first investigated the role of angiotensin II in the regulation of renal klotho gene expression. Long-term infusion of angiotensin II downregulated renal klotho gene expression at both the mRNA and protein levels. This angiotensin II-induced renal klotho downregulation was an angiotensin type 1 receptor-dependent but pressor-independent event. Adenovirus harboring mouse klotho gene (ad-klotho, 3.3x10(10) plaque forming units) was also intravenously administered immediately before starting angiotensin II infusion in some rats. This resulted in a robust induction of Klotho protein in the liver at day 4, which was still detectable 14 days after the gene transfer. Ad-klotho gene transfer, but not ad-lacZ gene transfer, caused an improvement of creatinine clearance, decrease in urinary protein excretion, and amelioration of histologically demonstrated tubulointerstitial damage induced by angiotensin II administration. Our data suggest that downregulation of the renal klotho gene may have an aggravative role in the development of renal damage induced by angiotensin II, and that induction of the klotho gene may have therapeutic possibilities in treating angiotensin II-induced end organ damage.
Hypertension 2002 Apr
PMID:In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. 1196 36

We previously identified a functional variant of KLOTHO (termed "KL-VS"), which harbors two amino acid substitutions in complete linkage disequilibrium and is associated with reduced human longevity when in homozygosity. Klotho-deficient mice display extensive arteriosclerosis when fed a normal diet, suggesting a potent genetic predisposition. To determine whether klotho influences atherosclerotic risk in humans, we performed cross-sectional studies to assess the association between the KL-VS allele and occult coronary artery disease (CAD) in two independent samples of apparently healthy siblings of individuals with early-onset (age <60 years) CAD (SIBS-I [N=520] and SIBS-II [N=436]). Occult CAD was defined as the occurrence of a reversible perfusion defect during exercise thallium scintigraphy and/or as an abnormal result of an exercise electrocardiogram (SIBS-I, n=97; SIBS-II, n=56). In SIBS-I, the KL-VS allele conferred a relative odds of 1.90 (95% confidence interval 1.21-2.98) for occult CAD, after adjusting for familial intraclass correlations (P<.005). Logistic regression modeling, incorporating known CAD risk factors, demonstrated that the KL-VS allele is an independent risk factor (P<.019) and that the imposed risk of KL-VS allele status is influenced by modifiable risk factors. Hypertension (P<.022) and increasing high-density lipoprotein cholesterol (HDL-C) levels (P<.022) mask or reduce the risk conferred by the KL-VS allele, respectively, whereas current smoking (P<.004) increases the risk. Remarkably concordant effects of the KL-VS allele and modifying factors on the risk of occult CAD were seen in SIBS-II. These results demonstrate that the KL-VS allele is an independent risk factor for occult CAD in two independent high-risk samples. Modifiable risk factors, including hypertension, smoking status, and HDL-C level, appear to influence the risk imposed by this allele.
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PMID:KLOTHO allele status and the risk of early-onset occult coronary artery disease. 1266 74

Pericytes are an integral component of blood capillaries, but their involvement in a variety of conditions and diseases, including hypertension and multiple sclerosis, is poorly understood. In order to analyze the mRNA expression of markers related to hypertension and multiple sclerosis in rat brain pericytes, we have established brain capillary pericyte cell lines from temperature-sensitive SV40 large T antigen transgenic rats. The newly established clones showed similar biochemical and morphological properties to primary pericytes. The expression of endothelial cell-related markers Flt-1, Flk-1, Tie-1, and Tie-2 was evaluated by RT-PCR analysis. beta2-Adrenergic receptor (beta2-AR), angiotensin II receptor type1A (AT1A), and klotho were also evaluated as markers related to hypertension and multiple sclerosis. All of the isolated clones expressed beta2-AR, AT1A and klotho genes. They also stably expressed Flt-1 and Tie-2, while Flk-1, Tie-1 and CXCR4 were expressed only at low levels in some of the clones. The expressions of AT1 in TR-PCT1 were determined by Western blotting. Angiotensin II stimulated migration of pericytes. This effect was blocked by an AT1 antagonist. The pericyte cell lines established here are pluripotent, and should be useful for analysis of the reactivity and biological roles of pericytes.
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PMID:Rat brain pericyte cell lines expressing beta2-adrenergic receptor, angiotensin II receptor type 1A, klotho, and CXCR4 mRNAs despite having endothelial cell markers. 1294 42

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses multiple aging phenotypes(e.g. arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, short lifespan). We have shown that mice deficient for the klotho gene show endothelial dysfunction as manifested by an attenuated response of aortic relaxation in response to acetylcholine stimulation. Nitric oxide production was also significantly reduced in klotho deficient mice. A decrease in klotho gene expression in animals under sustained circulatory and metabolic stress(e.g. atherosclerosis). The klotho gene delivery improves endothelial dysfunction through a pathway involving nitric oxide, and is involved in modulating vascular function(e.g. hypertension, vascular remodeling). Our findings establish the basis for the therapeutic potential of klotho gene delivery in atherosclerotic disease.
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PMID:[klotho gene]. 1473 37

Aging is a physiological process that causes structural and functional changes in human body systems, sometimes leading to various organ failure. As far as the kidney is concerned, both genetic factors and environmental agents may influence the tissues damage in elderly people and the related loss of function. On the other hand, functional adaptations to structural changes appear to be compromised by co-morbid conditions that are frequently found in elderly people, such as atherosclerosis and hypertension. It is not yet known whether physiological aging is inevitably accompanied by a decline in renal function or how rapidly it might happen. The discovery of molecular mechanisms responsible for tissue damage in aging could offer new perspectives on interventions. The role of nitric oxide, oxidative stress, the renin-angiotensin system, changes in length of telomeres, and klotho gene expression are important subjects for further in-depth studies about aging. A better understanding of physiological renal aging could improve the clinical approach to this process and widen the therapeutic possibilities offered by transplantation.
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PMID:Kidney aging: from phenotype to genetics. 1592 18


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