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)

Knowledge of transcription and translation has advanced our understanding of cardiac diseases. Here, we present the hypothesis that the stability of mRNA mediated by the 3'-untranslated region (3'-UTR) plays a role in changing gene expression in cardiovascular pathophysiology. Several proteins that bind to sequences in the 3'-UTR of mRNA of cardiovascular targets have been identified. The affected mRNAs include those encoding beta-adrenergic receptors, angiotensin II receptors, endothelial and inducible nitric oxide synthases, cyclooxygenase, endothelial growth factor, tissue necrosis factor (TNF-alpha), globin, elastin, proteins involved in cell cycle regulation, oncogenes, cytokines and lymphokines. We discuss: (a) the types of 3'-UTR sequences involved in mRNA stability, (b) AUF1, HuR and other proteins that bind to these sequences to either stabilize or destabilize the target mRNAs, and (c) the potential role of the 3'-UTR mediated mRNA stability in heart failure, myocardial infarction and hypertension. We hope that these concepts will aid in better understanding cardiovascular diseases and in developing new therapies.
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PMID:The role of 3'-untranslated region (3'-UTR) mediated mRNA stability in cardiovascular pathophysiology. 1169

Chronic heart failure is characterized by increased vascular systemic resistances secondary to activation of various vasoconstrictor systems and to decreased endothelium-dependent vasodilatation. Endothelial dysfunction, described both in animals and in humans, may be caused by an increased inactivation of nitric oxide (NO) by reactive oxygen species, leading to decreased NO bioavailability and impaired vasodilatation. Increased levels of free radicals in heart failure may result either from increased production or a decrease in the cellular antioxidant reserves. Free radicals are produced by three enzymatic systems: NADH/NADPH oxidase (after stimulation by angiotensin II or TNF-alpha), xanthine oxidase or endothelial NO-synthase (NOS) itself. However, oxidative stress alone cannot explain endothelial dysfunction. Other mechanisms involved in the regulation of the production of NO (e.g. decreased expression and/or activity of the NOS) and/or changes in production of vasoconstrictors may participate in this impaired endothelium-dependent vasodilatation in heart failure.
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PMID:[Oxidative stress and endothelial dysfunction in heart failure]. 1180 96

Insulin resistance and hyperinsulinemia have been observed in over 70% of the nonobese, nondiabetic subjects with essential hypertension (HT). Alpha-1 blockers, ACE-antagonists, long-acting Ca blockers including nifedipine CR, some form of beta-blockers, tilisolor, which is reported to increase blood flow, improve insulin sensitivity when blood pressure is better controlled. Decrease of serum potassium during insulin sensitivity test and intraplatelet free Ca2+ concentration is positively and negatively correlated with insulin sensitivity, respectively. Blood pressure is correlated with insulin resistance, which is also observed in secondary HT. The resistance is correlated with salt sensitivity as well as impaired nocturnal fall of blood pressure. These suggest the possible association of insulin resistance with altered intracellular cation metabolism. Insulin resistance and associated hyperinsulinemia have been observed in effort as well as vasospastic angina pectoris (VSAP), atherothrombotic cerebral infarction, and in ASO without obesity, HT, or diabetes, suggesting the resistance resulting from endothelial dysfunction. Insulin resistance has been observed in heart failure and is correlated with angiotensin II. Resistance is also observed in hypertrophic cardiomyopathy and is partially correlated with TNF-alpha. These results indicate that insulin resistance seem to be multifactorial. An effort to normalize insulin sensitivity is crucial to eliminate multiple risk factors as well as to prevent the progression of atherosclerotic vascular lesions.
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PMID:Multifactorial insulin resistance and clinical impact in hypertension and cardiovascular diseases. 1187 61

The cytokine tumor necrosis factor (TNF)-alpha has been causally linked to left ventricular (LV) remodeling, but the molecular basis for this effect is unknown. Matrix metalloproteinases (MMPs) have been implicated in cardiac remodeling and can be regulated by TNF-alpha. This study tested the central hypothesis that administration of a TNF-alpha blocking protein would prevent the induction of MMPs and alter the course of myocardial remodeling in developing LV failure. Adult dogs were randomly assigned to the following groups: 1) chronic pacing (250 beats/min, 28 days, n = 12), 2) chronic pacing with concomitant administration of a TNF-alpha blocking protein (TNF block) using a soluble p75 TNF receptor fusion protein (TNFR:Fc; administered at 0.5 mg/kg twice a week subcutaneously, n = 7), and 3) normal controls (n = 10). LV end-diastolic volume increased from control with chronic pacing (83 +/- 12 vs. 118 +/- 10 ml, P < 0.05) and was reduced with TNF block (97 +/- 9 ml, P < 0.05). MMP zymographic levels (92 kDa, pixels) increased from control with chronic pacing (36,848 +/- 9,593 vs. 87,247 +/- 12,912, P < 0.05) and was normalized by TNF block. Myocardial MMP-9 and MMP-13 levels by immunoblot increased with chronic pacing relative to controls (130 +/- 10% and 118 +/- 6%, P < 0.05) and was normalized by TNF block. These results provide evidence to suggest that TNF-alpha contributes to the myocardial remodeling process in evolving heart failure through the local induction of specific MMPs.
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PMID:TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling. 1189 63

Transgenic mice are widely used to study cardiac function, but strain-dependent differences in autonomic nervous system activity (ANSA) have not been explored. We compared 1) short-term pharmacological responses of cardiac rhythm in FVB vs. C57Black6/SV129 wild-type mice and 2) long-term physiological dynamics of cardiac rhythm and survival in tumor necrosis factor (TNF)-alpha transgenic mice with heart failure (TNF-alpha mice) on defined backgrounds. Ambulatory telemetry electrocardiographic recordings and response to saline, adrenergic, and cholinergic agents were examined in FVB and C57Black6/SV129 mice. In FVB mice, baseline heart rate (HR) was higher and did not change after injection of isoproterenol or atropine but decreased with propranolol. In C57Black6/SV129 mice, HR did not change with propranolol but increased with isoproterenol or atropine. Mean HR, but not indexes of HR variability, was an excellent predictor of response to autonomic agents. The proportion of surviving animals was higher in TNF-alpha mice on an FVB background than on a mixed FVB/C57Black6 background. The homeostatic states of ANSA are strain specific, which can explain the interstrain differences in mean HR, pharmacological responses, and survival of animals with congestive heart failure. Strain-specific differences should be considered in selecting the strains of mice used for transgenic and gene targeting experiments.
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PMID:Strain-specific patterns of autonomic nervous system activity and heart failure susceptibility in mice. 1200 14

Mitogen-activated protein kinase kinase kinase (MEKK1) mediates activation of c-Jun NH(2)-terminal kinase (JNK). Although previous studies using cultured cardiac myocytes have suggested that the MEKK1-JNK pathway plays a key role in hypertrophy and apoptosis, its effects in cardiac hypertrophy and apoptosis are not fully understood in adult animals in vivo. We examined the role of the MEKK1-JNK pathway in pressure-overloaded hearts by using mice deficient in MEKK1. We found that transverse aortic banding significantly increased JNK activity in Mekk1(+/+) but not Mekk1(-/-) mice, indicating that MEKK1 mediates JNK activation by pressure overload. Nevertheless, pressure overload caused significant levels of cardiac hypertrophy and expression of atrial natriuretic factor in Mekk1(-/-) animals, which showed higher mortality and lung/body weight ratio than were seen in controls. Fourteen days after banding, Mekk1(-/-) hearts were dilated, and their left ventricular ejection fraction was low. Pressure overload caused elevated levels of apoptosis and inflammatory lesions in these mice and produced a smaller increase in TGF-beta and TNF-alpha expression than occurred in wild-type controls. Thus, MEKK1 appears to be required for pressure overload-induced JNK activation and cytokine upregulation but to be dispensable for pressure overload-induced cardiac hypertrophy. MEKK1 also prevents apoptosis and inflammation, thereby protecting against heart failure and sudden death following cardiac pressure overload.
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PMID:The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy. 1212 19

Although the clinical picture of cardiac cachexia is well-known in patients with advanced chronic heart failure (CHF) the factors that determine who is at risk for this progressive catabolic syndrome and who is not remain unclear. Different endocrine systems have been accused of being involved in this process: an imbalance between catabolic and anabolic steroids with an elevated cortisol/dihydroepiandrosterone ratio, an increased resting metabolic rate due to high levels of circulating catecholamines, various cytokines are activated in CHF (i.e. TNF-alpha, IL-6, IL-1beta and others), and elevated levels of growth hormone (GH) with inappropriately normal or low serum levels of insulin-like growth factor-I (IGF-I) have been described in cardiac cachexia. These catabolic factors contribute to peripheral muscle atrophy, augment the expression of the inducible nitric oxide synthase (iNOS), which in turn inhibits the aerobic cellular metabolism. The present review examines whether the catabolic factors can be influenced by a classical anabolic intervention: regular physical exercise training. Long-term training programs increase skeletal muscle cytochrome c oxidase activity and are associated with reduced local expression of pro-inflammatory cytokines as well as iNOS, and augment local IGF-I production. In concert, these beneficial effects of exercise training may help to retard the catabolic process in CHF finally leading to cardiac cachexia and death.
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PMID:Chronic heart failure and skeletal muscle catabolism: effects of exercise training. 1216 19

The functional role of tumor necrosis factor (TNF)-alpha in the heart has been extensively studied over the last 15 years. Collectively, these studies have demonstrated that TNF-alpha has both diverse and potentially conflicting roles in cardiac function and pathology. These include beneficial effects, such as cardioprotection against ischemia, myocarditis, and pressure overload, as well as potentially adverse effects, such as the development of atherosclerosis, reperfusion injury, hypertrophy, and heart failure. TNF-alpha antagonist therapy recently has been demonstrated to be clinically applicable in inflammatory conditions, and clinical trials are currently in progress in the use of these agents in cardiovascular diseases. The scope for clinical applications of anti-TNF-alpha therapy in cardiovascular diseases is potentially extensive. Hence, this review has been undertaken to evaluate the cardiovascular effects of this pleiotropic cytokine and to evaluate the potential of targeting this cytokine in cardiovascular therapeutics. An overview of the TNF-alpha peptide and its associated signaling are described. This is followed by a discussion of the known roles of TNF-alpha in cardiac physiology and in a diverse array of cardiac pathologies. Reference to experimental and clinical studies using anti-TNF-alpha therapies are described where applicable. The postulated role of TNF-alpha signaling concerning innate cardiac cellular processes that may have direct adaptive effects in the heart will be reviewed with respect to future research directions. Finally, the author postulates that attenuation of TNF-alpha biosynthesis in selected individuals will need to be tested if true benefits of this therapeutic approach are to be realized in the management of cardiovascular diseases.
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PMID:Tumor necrosis factor-alpha in cardiovascular biology and the potential role for anti-tumor necrosis factor-alpha therapy in heart disease. 1219 98

Congestive heart failure is associated with hyperuricemia and elevations in the levels of circulating markers for inflammation. The purpose of this study was to assess the relationship between levels of serum uric acid, activity of the renin-angiotensin-aldosterone system and TNF-alpha in heart failure patients with respect to the extent of left ventricular dysfunction. Circulating uric acid, TNF-alpha, plasma renin activity and concentrations of aldosterone were measured in 30 patients with congestive heart failure, divided into subgroups according to their NYHA class (II-IV). We found a significant step-by-step increase in TNF-alpha among the subgroups. Significant differences among the subgroups were found for the values of uric acid and the values of plasma renin and aldosterone. Serum uric acid correlated significantly with TNF-alpha concentrations (r = 0.36, P < 0.05) leukocytes (r = 0.38, P = 0.03) and ejection fraction (r = 0.64, P < 0.01). No significant correlation was found between the activity of the renin-angiotensin-aldosterone system and uricemia (r = 0.34). In a multivariate model, uric acid concentration was predicted significantly by the ejection fraction and blood leukocytes, this relationship being independent of serum creatinine, treatment modality, age and gender. We conclude that serum uric acid may reflect the severity of systolic dysfunction and the activation of an inflammatory reaction in patients with congestive heart failure.
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PMID:Uric acid--a marker for systemic inflammatory response in patients with congestive heart failure? 1223 11

Side-stream cigarette smoke (SSCS), a major component of secondhand smoke, induces reactive oxygen species, which promote oxidative damage in tissues and organs. Inflammatory cytokines play an important role in the pathogenesis of atherosclerosis and heart failure. The present 4-month study examined the effect of various chronic SSCS exposure levels on splenic inflammatory cytokine secretion, heart contractile function, and pathology at 60- and 120-min per day, 5 days per week, for a total of 16 weeks. Tissue vitamin E level and lipid peroxide production also were tested to estimate the oxidative stress. The study found that the pro-inflammatory cytokines, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and IL-1beta, significantly increased in 120-min SSCS-exposed mice. Decreased stroke volume and increased peripheral arterial resistance were observed in mice exposed to 120-min SSCS per day. Heart pathology was only found in 120-min SSCS-exposed mice. Cardiac and hepatic antioxidant vitamin E levels were decreased as a result of oxidative stress. Hepatic lipid peroxides were increased upon 60-min SSCS exposure. The data also demonstrated that the cardiac alpha-tocopherol level has a strong correlation with stroke volume; splenic IL-1beta has a strong negative correlation with stroke volume; splenic TNF-alpha has a very strong negative correlation with stroke volume. In conclusion, SSCS exposure induced systemic inflammatory responses. SSCS exposure also accentuated systemic lipid peroxidation with depletion of cardiac and hepatic antioxidant vitamin E level. Finally, SSCS exposure at 120 min per day decreased stroke volume and increased vascular resistance. Systemic IL-1beta and TNF-alpha production are responsible for heart contractile dysfunction. Free radicals may be responsible for the progression to heart contractile dysfunction induced, in part, by SSCS. Oxidized lipoprotein could contribute to the vascular functional changes. Exploring the mechanism of vascular dysfunction in mice is warranted. A more precise quantification of the smoking exposure dose in mice needs to be determined as well.
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PMID:Side-stream cigarette smoke induces dose-response in systemic inflammatory cytokine production and oxidative stress. 1232 64


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