Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In experimental models where chronic inappropriate (relative to sodium intake and intravascular volume) elevations in circulating mineralocorticoids (aldosterone or deoxycorticosterone) are created, a reactive fibrosis with vascular remodeling is observed in systemic organs and the heart. Until recently, it was assumed that aldosterone was derived solely from adrenal glands via the circulation; however, there is now convincing evidence that cells of the heart and vasculature express genes responsible for the formation of both aldosterone and corticosterone and are capable of producing these steroids. Vascular endothelial and smooth muscle cells express CYP11B1 and CYP11B2, genes responsible for 11 beta -hydroxylase and aldosterone synthase, respectively. Furthermore, smooth muscle cells elaborate aldosterone. There is evidence that similar regulatory mechanisms operate in vascular cells as in adrenal cortex, since aldosterone synthase and 11 beta -hydroxylase expression are differentially modulated by low sodium/high potassium, angiotensin II and ACTH. It is likely that such localized corticosteroid production also occurs at sites of tissue repair, where populations of collagen-producing myofibroblasts, nourished by a neovasculature, predominate. Using a subcutaneous pouch model of granulation tissue we have obtained compelling data which would support such a notion. The mineralocorticoid receptor antagonist, spironolactone, severely attenuates pouch formation over a 2-week period and significantly reduces pouch wall hydroxyproline concentration. This effect is apparent even following adrenalectomy, when circulating corticosteroids are undetectable; however, with adrenalectomy alone, pouch formation is barely affected. This we took to be a possible indication of an effect of local, non-adrenal steroids in maintaining pouch tissue. Spironolactone inhibits angiogenesis. A recent clinical study demonstrates the efficacy of low-dose spironolactone in enhancing survival in patients with advanced chronic cardiac failure. Although it is not known how spironolactone brings about such an improvement in survival, we would propose that inhibition of fibrous tissue formation and/or angiogenesis might be important contributory factors. Further studies are required to address the relative contributions of circulating vs local aldosterone in promoting normal vs pathologic connective tissue formation.
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PMID:Extra-adrenal mineralocorticoids and cardiovascular tissue. 1037 93

Monitoring of 24-hour ambulatory blood pressure(ABPM), measurements of circulating vasoactive substances and microalbuminuria, and assessment of gene polymorphisms as genetic markers are introduced to detect and evaluate hypertension. Classifications of ABPM based on impact on risks of cardiovascular diseases have been currently available. Plasma level of brain natriuretic peptide(BNP), a cardiac hormone, increases markedly in congestive heart failure, in proportion to its severity, and is evaluated as a potential index of severity of heart failure. In addition, serum level of hepatocyte growth factor(HGF), a member of endothelium specific growth factors, in hypertension might be useful for evaluating the presence of complications and degree of endothelial dysfunction. In diabetes mellitus, onset of microalbuminuria appeared as an important sign of early nephropathy. There is growing evidence that microalbuminuria is an independent predictor of atherosclerosis and premature death in the general population. Current studies have shown that gene polymorphisms including components of the renin-angiotensin-aldosterone system may be possible genetic markers for hypertension and its associated cardiovascular diseases. Our data suggest positive linkages between hypertension and 4 gene polymorphisms including angiotensinogen Met235Thr, angiotensin converting enzyme I/D, aldosterone synthase CYP11B2 T-344C, and endothelial nitric oxide synthase Glu298Asp in the Aomori population.
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PMID:[New techniques and laboratory examinations in the detection and evaluation of hypertension]. 1130 25

The pathway of tissue aldosterone production may exist in the heart, and may be an important contributory factor to myocardial fibrosis and cardiac remodelling in the failing heart. CYP11B2 (aldosterone synthase) catalyses the final step of aldosterone production. The aim of the present study was to determine whether CYP11B2 and CYP11B1 (11beta-hydroxylase) are expressed in myocardial tissues, and whether these enzymes contribute to collagen accumulation and myocardial dysfunction in the failing human heart. Endomyocardial tissues were obtained from 23 patients with chronic heart failure (CHF) and 10 controls. CYP11B2 and CYP11B1 mRNA levels were measured by real-time quantitative reverse transcriptase-PCR. The myocardial collagen volume fraction (CVF) was determined by digital planimetry. CYP11B2 mRNA expression was greater in the CHF group than in the controls (P<0.05), while CYP11B1 mRNA was barely expressed in either group. There was a positive correlation between CYP11B2 mRNA levels and CVF (r=0.64, P=0.001). CYP11B2 mRNA was particularly highly expressed in subgroups of CHF patients with a large left ventricular end-systolic diameter (>55 mm) or a low left ventricular ejection fraction (<30%). CYP11B2 mRNA expression and CVF were lower in a CHF subgroup treated with a combination of spironolactone and angiotensin-converting enzyme inhibitors (ACEIs) than in a subgroup not treated with these drugs. In conclusion, this study has shown that increased myocardial expression of CYP11B2 mRNA is associated with increased myocardial fibrosis and with the severity of left ventricular dysfunction in human CHF. In addition, CYP11B2 expression and cardiac fibrosis are found to be decreased in CHF patients on drug therapy comprising spironolactone combined with ACEIs.
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PMID:Aldosterone synthase (CYP11B2) expression and myocardial fibrosis in the failing human heart. 1191 99

We have shown that aldosterone, previously thought to be synthesized solely in the adrenal cortex, is also produced in the failing human heart. One way to induce aldosterone synthesis in the heart would be to increase the expression of CYP11B2, the enzyme catalyzing the terminal step in aldosterone synthesis. However, CYP11B2 expression has never been examined in cardiac tissue from patients with heart failure. We assayed CYP11B2 expression in left ventricular tissue obtained at autopsy from seven patients. Total RNA was extracted from frozen samples. CYP11B2 gene expression was then quantitatively analyzed using a modified real-time PCR method that enabled assay of samples containing very small amounts of template DNA. The template DNA was initially amplified 1024-fold by subjecting it to 10 PCR cycles in the absence of the TaqMan probe. Thereafter, conventional real-time PCR was simultaneously performed on both target and standard samples. We measured the small quantities of CYP11B2 gene transcript and found the levels to be significantly higher in samples from heart failure patients than in those from cardiovascular disease-free patients. Our modified real-time PCR method enables quantitative analysis of gene expression using very small amounts of template DNA. CYP11B2 expression is up-regulated in the failing human heart.
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PMID:Expression of aldosterone synthase gene in failing human heart: quantitative analysis using modified real-time polymerase chain reaction. 1216 36

Aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) catalyze the production of aldosterone and corticosterone, respectively, in the rat adrenal cortex. Recently, there has been some debate as to whether these corticosteroids are also produced in the hearts of rodents and humans, possibly contributing to the development of hypertrophy and myocardial fibrosis. To investigate this, we have used our established, highly sensitive real-time quantitative RT-PCR method to measure CYP11B1 and CYP11B2 mRNA levels in adrenal and cardiac tissue from several rat models of cardiovascular pathology. We have also studied isolated adult rat ventricular myocytes treated with angiotensin II and ACTH. Total RNA was isolated from the adrenal and cardiac tissue of 1) male Wistar rats with heart failure induced by coronary artery ligation and sham-operated controls; 2) stroke-prone spontaneously hypertensive rats and Wistar Kyoto rats as controls; 3) cyp1a1Ren-2 transgenic rats and Fischer controls; 4) isolated adult Sprague-Dawley ventricular myocytes incubated with 11-deoxycorticosterone (DOC), DOC plus angiotensin II, or DOC plus ACTH. Adrenal CYP11B2 expression was significantly increased in transgenic rats compared with Fischer controls (1.3 x 10(9)+/- 1.2 x 10(9) vs. 2.1 x 10(7) +/- 7.0 x 10(6) copies/microg RNA; P < 0.05). There were no other significant differences in adrenal CYP11B2 or CYP11B1 expression between the model animals and their respective controls. Cardiac CYP11B1 and CYP11B2 mRNA transcript levels from all in vivo and in vitro groups were never greater than 100 copies per microgram total RNA and therefore too low to be detected reproducibly. This suggests that cardiac corticosteroid production is unlikely to be of any physiological or pathological significance.
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PMID:The aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) genes are not expressed in the rat heart. 1617 17

Aldosterone may play a pivotal role in the pathophysiology of heart failure. To elucidate the beneficial cardioprotective mechanism of eplerenone, a novel selective aldosterone blocker, we hypothesized that eplerenone stimulates endothelial NO synthase (eNOS) through Akt and inhibits inducible NO synthase (iNOS) via nuclear factor kappaB (NF-kappaB) after the development of oxidative stress and activation of the lectin-like, oxidized, low-density lipoprotein receptor 1 (LOX-1) pathway in Dahl salt-sensitive rats with heart failure. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of the left ventricular hypertrophy stage (11 weeks) to the failing stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship was evaluated using a conductance catheter. Decreased percentage of fractional shortening by echocardiography and end-systolic pressure-volume relationship in failing rats was significantly ameliorated by eplerenone. Downregulated eNOS expression, eNOS and Akt phosphorylation, and NOS activity in failing rats were increased by eplerenone. Upregulated expression of the mineralocorticoid receptor aldosterone synthase (CYP11B2); NAD(P)H oxidase p22phox, p47phox, gp91phox, iNOS, and LOX-1; and activated p65 NF-kappaB, protein kinase CbetaII, c-Src, p44/p42 extracellular signal-regulated kinase, and p70S6 kinase phosphorylation were inhibited by eplerenone. Eplerenone administration resulted in significant improvement of cardiac function and remodeling and upregulation of sarcoplasmic reticulum Ca(2+)-ATPase expression. These findings suggest that eplerenone may have significant therapeutic potential for heart failure, and these cardioprotective mechanisms of eplerenone may be mediated in part by stimulating eNOS through Akt and inhibiting iNOS via NF-kappaB after activation of the oxidative stress-LOX-1 pathway and signal transduction pathway.
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PMID:Cardioprotective mechanisms of eplerenone on cardiac performance and remodeling in failing rat hearts. 1650 12

Cardiac aldosterone levels have not been evaluated in diastolic heart failure (DHF), and its roles in this type of heart failure remain unclear. This study aimed to detect cardiac aldosterone by use of a liquid chromatographic-mass spectrometric method and to assess the effects of mineralocorticoid receptor blockade on hypertensive DHF. Dahl salt-sensitive rats fed 8% NaCl diet from 7 wk (hypertensive DHF model) were divided at 13 wk into three groups: those treated with subdepressor doses of eplerenone (12.5 or 40 mg x kg(-1) x day(-1)) and an untreated group. Dahl salt-sensitive rats fed 0.3% NaCl diet served as controls. Cardiac aldosterone was detected in the DHF rats but not in the control rats, with increased ventricular levels of mineralocorticoid receptor. Cardiac levels of 11-deoxycorticosterone, corticosterone, and 11-dehydrocorticosterone were not different between the control and DHF rats, but the tissue level of corticosterone that has an affinity to mineralocorticoid receptor was 1,000 times as high as that of aldosterone. Aldosterone synthase activity and CYP11B2 mRNA were undetectable in the ventricular tissue of the DHF rats. Administration of eplerenone attenuated ventricular hypertrophy, ventricular fibrosis, myocardial stiffening, and relaxation abnormality, leading to the prevention of overt DHF. In summary, the myocardial aldosterone level increased in the DHF rats. However, its value was extremely low compared with corticosterone, and no evidence for enhancement of intrinsic myocardial aldosterone production was found. The upregulation of mineralocorticoid receptor may play a central role in the pathogenesis of DHF, and blockade of mineralocorticoid receptor is likely an effective therapeutic regimen of DHF.
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PMID:Elevated cardiac tissue level of aldosterone and mineralocorticoid receptor in diastolic heart failure: Beneficial effects of mineralocorticoid receptor blocker. 1702 67

A common polymorphism exists for the aldosterone synthase (CYP11B2) gene at position 344 (C-344-T). The 344-C allele has been associated with increased aldosterone synthase activity. We hypothesized that the aldosterone synthase gene polymorphism is associated with adverse cardiac remodeling in an ambulatory, chronic heart failure population. The CYP11B2 C-344T genotype was determined in 104 patients with heart failure who were in New York Heart Association classes I to IV, had left ventricular ejection fractions <40%, and were prospectively recruited from an urban heart failure clinic (65% African-American, 69% had a nonischemic cause, with a mean left ventricular ejection fraction of 22 +/- 9%). The 344-C allele frequency was 0.34 (45.2% TT, 42.3% CT, and 12.5% CC) and was significantly lower in African-American (0.27) versus Non-African-American patients (0.44, p = 0.018). Baseline and 1-year follow-up echocardiograms were obtained in 74 patients. Improvement was defined as a decrease in left ventricular end-systolic diameter (LVESD). At follow-up, the 344-C allele was associated with improved LVESD (p = 0.013). In addition, analysis by race showed that this effect was observed only in African-American patients (p <0.006). In multivariate logistic regression, controlling for cause, gender, and spironolactone use, the TT genotype (i.e., absence of 344-C allele) was associated with a fivefold lower rate of improvement in LVESD in African-Americans (p = 0.014). In conclusion, the 344-C allele of the aldosterone synthase gene polymorphism was associated with improved cardiac remodeling over time for African-Americans with chronic systolic heart failure. Although this genetic-driven increase in aldosterone activity should predispose to worse cardiac remodeling, it may represent a more susceptible state and enhanced response to therapy in this racial subgroup.
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PMID:Usefulness of the aldosterone synthase gene polymorphism C-344-T to predict cardiac remodeling in African-Americans versus non-African-Americans with chronic systolic heart failure. 1763 Oct 84

Aldosterone plays an important role in the regulation of electrolyte and water homeostasis and in blood pressure maintenance. The latest studies have revealed involvement of this hormone in the development of myocardium hypertrophy and fibrosis, with heart failure progression, vessel remodeling, and atherogenesis. The crucial enzyme in aldosterone production is aldosterone synthase, which catalyses the last three steps of its synthesis. It was reported in many studies that polymorphisms of the gene encoding aldosterone synthase, CYP11B2, especially the -344C/T polymorphism, are associated with cardiovascular diseases. This article is a short review of research on the role of the CYP11B2-344C/T polymorphism in hypertension, heart muscle remodeling, and especially in atherogenesis. Information about the molecular basis of aldosterone's synthesis, action, and significance, especially in heart failure, is also provided.
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PMID:[The role of the -344C/T polymorphism of the aldosterone synthase gene (CYP11B2) in cardiovascular diseases]. 1820 94

We analyzed the possible association between aldosterone synthase (CYP11B2) T-344C polymorphism, which is associated with increased aldosterone activity, and the prevalence of atrial fibrillation (AF) in 196 consecutive patients who had symptomatic systolic heart failure (HF; left ventricular ejection fraction <40%) for > or =3 months before recruitment. Genomic DNA was extracted from peripheral blood leukocytes using a standard protocol. Subjects were genotyped for the CYP11B2 polymorphism using the polymerase chain reaction/restriction fragment length polymorphism approach. AF was present in 63 patients (33%) with HF. We found the -344 CC genotype to be a strong independent marker for AF. Almost 1/2 (45%) of patients with this genotype had AF compared with 1/4 (27%) with -344 TT and TC genotypes (p = 0.01). A multivariate stepwise logistic regression model that included age, gender, New York Heart Association class, CYP11B2 -344CC genotype, and echocardiographic measurements of left ventricular ejection fraction, left atrial dimension, left ventricular end-diastolic diameter, and mitral regurgitation severity showed that the CYP11B2 CC genotype (adjusted for age and left atrial size) was an independent predictor of AF (adjusted odds ratio 2.35, 95% confidence interval 1.57 to 3.51, p = 0.03). In conclusion, CYP11B2 T-344C promoter polymorphism predisposes to clinical AF in patients with HF.
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PMID:Aldosterone synthase gene polymorphism as a determinant of atrial fibrillation in patients with heart failure. 1863 95


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