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 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell biology is in transition from reductionism, to a more integrated science which is now preoccupied by molecular interactions acting in modules. Large-scale quantitative analysis of gene expression, including cDNA microarrays and proteomic analysis, is now applied to heart failure and atherosclerosis. The technology is still at the beginning and is limited by variations in the array platforms and gene products as well as sensitivity or specificity of the selected probes. These limitations are progressively going to be reduced, but still they do exist. Biological systems are scale free networks made from genes, proteins or traits that interact one another and form networks and functional modules. Networks emerge through the addition of new nodes which are preferentially attached to more connected nodes to form hubs, according to the "rich-gets-richer" mechanism, and there are large networks which include central genes (nexus). Both hubs and nexus are attractive candidate for targeting new therapy. An important study from King JY et al. (Physiol Genomics 2005; 23: 103-18) exemplifies this concept by showing the first realistic pathways to understand atherosclerosis. The 4 steps of the design are based on histological grading and microarrays analysis and include an association network constructed from PubMed and the construction of sub-networks in which genes whose expression was differentially regulated were indicated. Connectivity analysis networks revealed new important modular pathways. In heart failure, no attempts have been made to organize the data into functional modulus. Since the causes of heart failure are well documented, the problem is to identify functional modules responsible for myocardial dysfunction. Several potential functional modules can be identified so far. Indeed, cardiac remodeling results from two types of changes in gene expression, namelly the reexpression of the foetal programme which has a mechanical origin and several well documented interfering determinants that modified the basic remodelling, including senescence, obesity, diabetes, ischemia, and the neurohormonal reaction.
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PMID:From molecular to modular cardiology. How to interpret the millions of data that came out from large scale analysis of gene expression? 1661 26

In chronic heart failure of CAD, therapeutic approach will be available either with drugs or exercise. With exercise, coronary risk factors such as BP, lipid, DM and obesity will be controlled. In addition, ischemia will also be controlled by decreasing oxygen demand related to BP and HR, and with increasing oxygen supply by increased ECNOS gene expression, collateral formation and regression of coronary stenosis. Infarct size is also reported to be decreased by increasing MnSOD in the cell by exercise. Prognosis of CHF is also good in various evidence of exercise therapy. Recent advances of molecular biology have revealed various mechanisms of exercise effect. Thus, exercise if properly prescribed without provoking ischemia will be basically and clinically effective therapy for patients with CHF.
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PMID:[Exercise therapy for heart failure]. 1668 81

Cardiac phenotypic plasticity (so-called cardiac remodelling, CR) is characterized by changes in myocardial structure that happen in response to either mechanical overload or a loss of substance such as that occurring after myocardial infarction. Mechanosensation is a widespread biological process and is inextricably mixed with other transduction systems from hormones and vasopeptides, which ultimately produce post-translational modifications of transcription factors. The expression of the four main transcription factors during cardiogenesis is also enhanced as a link to foetal reprogramming. CR results from re-expression of the foetal programme, which is mostly adaptive, but also from several other phenotypic modifications that are not usually adaptive, such as fibrosis. (i) The initial determinant is mechanical, and re-expression of the foetal programme includes a global increase in genetic expression with cardiac hypertrophy, re-expression of genes that are normally not expressed in the adult ventricles, repression of genes not expressed during the foetal life, and activation of pre-exisiting stem cells. Microarray technology has revealed a coordinated change in expression of genes pertaining to signal transduction, metabolic function, structure and motility, and cell organism defence. The physiological consequence is a better adapted muscle. (ii) During clinical conditions, the effects of mechanics are modified by several interfering determinants that modify CR, including senescence, obesity, diabetes, ischemia and the neurohormonal reaction. Each of these factors can alter myocardial gene expression and modify molecular remodelling of mechanical origin. Finally, as compared to evolutionary phenotypic plasticity described in plants and insects in response to variations in environmental conditions, in CR, the environmental factor is internal, plasticity is primarily adaptive, and it involves coordinated changes in over 1400 genes. Study of reaction norms showed that the genotypes from different animal species are similarly plastic, but there are transgenic models in which adaptation to mechanics is not caused by hypertrophy but by qualitative changes in gene expression.
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PMID:Phenotypic plasticity of adult myocardium: molecular mechanisms. 1673 8

Obesity-related disorders are closely associated with the pathogenesis of cardiovascular disease. Adiponectin is a circulating adipose tissue-derived hormone that is down-regulated in obese individuals. Hypoadiponectinemia has been identified as an independent risk factor for type 2 diabetes, coronary artery disease, and hypertension, and experimental studies show that adiponectin plays a protective role in the development of insulin resistance, atherosclerosis, and inflammation. More recent findings have shown that adiponectin directly affects signaling in myocardial cells and exerts beneficial actions on the heart after pressure overload and ischemia-reperfusion injury. This review focuses on the role of adiponectin in the regulation of myocardial remodeling and acute cardiac injury.
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PMID:Cardioprotection by adiponectin. 1678 46

Recent studies highlighted the 'obesity paradox' after revascularization, suggesting a 'cardioprotective' effect of obesity. We assessed the association of BMI and regional wall motion score (RWMS) and peak CK and cTnI values (markers of infarct size) and 30-day survival among consecutive first ST-segment-elevation myocardial infarction patients who underwent successful primary PCI. Of the 164 patients, we found no difference in infarct size among the different groups, BMI < or = 25 kg/m2, 25 < BMI < or = 30 kg/m2, and BMI > 30 kg/m2, and no association between BMI as continuous variable and these variables. Thirty-day death rates were not statistically different among the three groups (10, 5, 2%, respectively, P = 0.83). Increased BMI does not confer any protective effect on the heart during acute ischemia.
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PMID:Is increased body mass index associated with a cardioprotective effect after ST-segment-elevation myocardial infarction? 1688 73

Obstructive sleep apnea (OSA) is characterised by repetitive episodes of upper airway occlusion during sleep. OSA has been shown to be associated with a variable degree of nasal inflammation, uvula mucosal congestion and airway hyperreactivity. The upper airway inflammation, whose clinical importance is uncertain, is characterised by leukocytes infiltration and interstitial oedema. In addition, recent data has shown the presence of neutrophilic inflammation in the lower airways. The current opinion is that airway inflammation is caused by the local, repeated mechanical trauma related to the intermittent airway occlusion typical of the disease. Another potential mechanism involves the intermittent nocturnal hypoxemia that through the phenomenon of the ischemia-reperfusion injury may induce the production of oxygen free radicals and therefore cause local and systemic inflammation. Finally, a state of low-grade systemic inflammation may be related to obesity per se with the pro-inflammatory mediators synthesised in the visceral adipose cells. Several authors stress the role of circulating and local inflammatory mediators, such as pro-inflammatory cytokines, exhaled nitric oxide, pentane and 8-isoprostane as the determinants of inflammation in OSA.
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PMID:Airway inflammation in patients affected by obstructive sleep apnea. 1691 81

Several studies report that blood pressure is increased in victims of Alzheimer's disease (AD) decades before the onset of the disease. Years before onset of Alzheimer's disease, blood pressure start to decrease and continues to decrease during the disease process. High blood pressure has also been related to pathological manifestations of Alzheimer's disease (senile plaques, neurofibrillary tangles, hippocampal atrophy). The exact mechanism behind these associations is not clear. Hypertension is also a risk factor for stroke, ischemic white matter lesions, silent infarcts, general atherosclerosis, myocardial infarction and cardiovascular diseases, and often clusters with other vascular risk factors, including diabetes mellitus, obesity and hypercholesterolemia. Also these risk factors have been related to Alzheimer's disease. Hypertension may thus cause cerebrovascular disease that may increase the possibility for individuals with AD encephalopathy to express a dementia syndrome. Hypertension may also lead to vessel wall changes in the brain, leading to hypoperfusion, ischemia and hypoxia which may initiate the pathological process of AD. Finally, subclinical AD may lead to increased blood pressure, and similar biological mechanisms may be involved in the pathogenesis of both disorders. Hypertension is a common disorder and often untreated. Several observational studies have reported that use of antihypertensives decreases risk of AD. Even though hypertension only results in a moderately increased risk of AD, or overall dementia, better treatment of hypertension may have an immense effect on the total number of demented individuals.
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PMID:Update on hypertension and Alzheimer's disease. 1694 11

Mitochondrial research is presently one of the fastest growing disciplines in biomedicine. Since the early 1990s, it has become increasingly evident that mitochondrial dysfunction contributes to a large variety of human disorders, ranging from neurodegenerative and neuromuscular diseases, obesity, and diabetes to ischemia-reperfusion injury and cancer. Most remarkably, mitochondria, the "power house" of the cell, have also become accepted as the "motor of cell death" reflecting their recognized key role during apoptosis. Based on these recent exciting developments in mitochondrial research, increasing pharmacological efforts have been made leading to the emergence of "Mitochondrial Medicine" as a whole new field of biomedical research. The identification of molecular mitochondrial drug targets in combination with the development of methods for selectively delivering biologically active molecules to the site of mitochondria will eventually launch a multitude of new therapies for the treatment of mitochondria-related diseases, which are based either on the selective protection, repair, or eradication of cells. Yet, while tremendous efforts are being undertaken to identify new mitochondrial drugs and drug targets, the development of mitochondria-specific drug carrier systems is lagging behind. To ensure a high efficiency of current and future mitochondrial therapeutics, colloidal vectors, i.e., delivery systems, need to be developed able to selectively transport biologically active molecules to and into mitochondria within living human cells. Here we review ongoing efforts in our laboratory directed toward the development of different phospholipid- and non-phospholipid-based mitochondriotropic drug carrier systems.
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PMID:Liposomes and liposome-like vesicles for drug and DNA delivery to mitochondria. 1695 79

Insulin resistance (IR) precedes the onset of Type 2 diabetes, but its impact on preconditioning against myocardial ischemia-reperfusion injury is unexplored. We examined the effects of diazoxide and ischemic preconditioning (IPC; 5-min ischemia and 5-min reperfusion) on ischemia (30 min)-reperfusion (240 min) injury in young IR Zucker obese (ZO) and lean (ZL) rats. ZO hearts developed larger infarcts than ZL hearts (infarct size: 57.3 +/- 3% in ZO vs. 39.2 +/- 3.2% in ZL; P < 0.05) and also failed to respond to cardioprotection by IPC or diazoxide (47.2 +/- 4.3% and 52.5 +/- 5.8%, respectively; P = not significant). In contrast, IPC and diazoxide treatment reduced the infarct size in ZL hearts (12.7 +/- 2% and 16.3 +/- 6.7%, respectively; P < 0.05). The mitochondrial ATP-activated potassium channel (K(ATP)) antagonist 5-hydroxydecanoic acid inhibited IPC and diazoxide-induced preconditioning in ZL hearts, whereas it had no effect on ZO hearts. Diazoxide elicited reduced depolarization of isolated mitochondria from ZO hearts compared with ZL (73 +/- 9% in ZL vs. 39 +/- 9% in ZO; P < 0.05). Diazoxide also failed to enhance superoxide generation in isolated mitochondria from ZO compared with ZL hearts. Electron micrographs of ZO hearts revealed a decreased number of mitochondria accompanied by swelling, disorganized cristae, and vacuolation. Immunoblots of mitochondrial protein showed a modest increase in manganese superoxide dismutase in ZO hearts. Thus obesity accompanied by IR is associated with the inability to precondition against ischemic cardiac injury, which is mediated by enhanced mitochondrial oxidative stress and impaired activation of mitochondrial K(ATP).
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PMID:Myocardial preconditioning against ischemia-reperfusion injury is abolished in Zucker obese rats with insulin resistance. 1700 56

Autoimmune or type 1 diabetes mellitus (T1DM), accounts for 90-95% of all cases of diabetes, while type 2 diabetes mellitus (T2DM), characterized by impaired insulin sensitivity and production, accounts for the other 5-10%. Atherosclerotic process starts during childhood and recognize several mechanisms that are activated in response to NOXIUS STIMULI and participate in a complex state which is accepted to be a chronic inflammatory state. T1DM patients, especially those with a non-optimal metabolic control, have a higher risk of developing all macrovascular complications such as myocardial infarction, stroke and silent ischemia. Macrovascular disease is mainly associated with hyperglycemia, dyslipidemia, obesity, hypertension, hypercoagulable state, cigarette smoking, lack of exercise, endothelial dysfunction, hyperhomocysteinemia and vascular wall abnormalities. In this paper we review the importance of traditional and non-traditional risk factors for macrovascular complications in children with T1DM and discuss their role in the pathogenesis of the excess cardiovascular mortality in these patients.
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PMID:Macroangiopathy in adults and children with diabetes: risk factors (part 2). 1711 Dec 97


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