Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High plasma plasminogen-activator inhibitor-1 (PAI-1) concentrations have been reported in coronary artery disease and stroke. We therefore, prospectively studied the association of PAI-1 with early target organ damage in patients with arterial hypertension has not been clearly established. We therefore investigated 136 subjects, 64 males and 72 females, mean age 50.0 +/- 12.3 years, with newly diagnosed essential hypertension who were free of cardiovascular events and were not receiving any antihypertensive medication. Plasma PAI-1 levels were measured by an ELISA method (STAGO). The study population was divided into two groups, group A with PAI-1 levels below 40 ng/mL and group B with more than 40 ng/mL. The left ventricular mass was calculated according to the formula of Devereux and was normalized by the individual's body surface area (LVM/BSA). Carotid intima-media thickness (IMT) was determined by ultrasonography. Microalbuminuria was assessed by an immunoturbidimetric method (SERA-PAK). Group A consisted of 89 individuals with hypertension (65.4%), 41 males and 48 females and group B of 47 individuals with hypertension (34.6%), 21 males and 26 females. Individuals in group B exhibited significantly higher LVM/BSA than individuals in group A (155.9 +/- 23.1 g/m2 vs. 129.7 +/- 32.2g/m2, respectively, p = 0.004) and increased IMT (0.97 +/- 0.20mm vs. 0.87 +/- 0.21 mm, respectively, p < 0.001). Microalbumin excretion rate was greater in group B than group A (70.9 +/- 84.4 mg/24 hrs vs. 20.9 +/- 45.1 mg/24 hrs, respectively, p = 0.002). In conclusion, elevated PAI-1 levels are associated with target organ damage in subjects with newly diagnosed arterial hypertension. Thus, it can be postulated that this fibrinolytic inhibitor may characterize hypertensives in the early stages of the atherothrombotic process.
 ...
PMID:Increased plasma plasminogen activator inhibitor-1 levels: a possible marker of hypertensive target organ damage. 1259 20

Etiopathogenesis of arterial hypertension and coronary disease involves interaction of numerous exogenous factors which determine the clinical course and therapeutic response in genetically predisposed individuals. The role of numerous cardiovascular risk factors has been reevaluated during the past few years, yet some unresolved issues and gaps still remain. One of the still insufficiently studied factors is lipoprotein (a) [Lp (a)] which belongs to a subclass of LDL lipoproteins. Its important component is apolipoprotein (a) which is structurally similar to plasminogen. This characteristic can be followed through evolution and is probably crucial for its physiologic but also pathophysiologic role. Actually, through its competition with plasminogen, Lp (a) interferes with the process of fibrinolysis and may contribute to tissue healing and restoration but also support and accelerate atherothrombotic process. Lp (a) concentration is stable and genetically determined in an individual and the indication that persons with elevated levels are permanently exposed to increased risk is supported by the data on twofold incidence of myocardial infarction in mothers of children with highest Lp (a) concentrations. Apart from competing with plasminogen via apolipoprotein (a), Lp (a) increases the activity of inhibitors of plasminogen-I activator and reduces the activity of transforming growth factor-beta. This results both in the absence of fibrinolysis and promotion of migration and proliferation of media smooth muscle cells, which are important in the onset of atherosclerotic process. Lp (a) binds to elastin via apolipoprotein B, resulting in oxidation and facilitated entry into macrophages and their transition into the so-called foam cells, also an important sign of early atherosclerosis. Although many pathophysiologic processes by which Lp (a) contributes to atherosclerosis have also been confirmed by animal experiments as well as by the presence of histologic evidence, clinical significance of elevated Lp (a) concentration is still questionable. However, results of prospective studies and metaanalyses were published few months ago and identified decisively Lp (a) as a factor that increases cardiovascular risk primarily in patients in whom other risk factors were also present. According to currently prevailing attitude, routine determination of Lp (a) is not justified and, according to most authors, its determination is useful in patients who had a cardiovascular incident at the age under 55 years, in those with recurrent coronary stenosis, or those with positive family history of such incidents. As Lp (a) is genetically determined, its detection in the early stages of essential hypertension might be a useful prognostic marker but a period of observation is still necessary for correct selection of hypertensive patients. Apart from the observation that hormone replacement therapy significantly decreases the Lp (a) level, there is currently no information on the effectiveness of either dietary or drug therapy. Due to Lp (a) antifibrotic effects, small aspirin doses may be beneficial to these patients, as well as B complex vitamins since hyperhomocysteinemia enhances atherogenicity of Lp (a). Therapeutic approach to patient with increased Lp (a) levels is currently based on as strict regulation of arterial pressure, glycemia and other dislipidemias as possible. In the present clinical practice, the elevated level of this lipoprotein indicates a patients with elevated cardiovascular risk, regardless of the fact whether Lp (a) is only a marker or an active factor of pathophysiologic process. Increased Lp (a) concentration may refer to the need for therapy, frequent monitoring and determination of even stricter aims for these individuals by selecting metabolically neutral and best tolerated drugs.
 ...
PMID:[Lipoprotein (a)--a mysterious factor in atherogenesis]. 1267 78

Familial Combined Hyperlipidemia is the most frequent familial hyperlipidemia with a high risk a early manifestation of arteriosclerosis. Endothelial dysfunction is the first step in the development of arteriosclerosis. The aim of our investigation was to examine selected markers of endothelial dysfunction in hyperlipidemic members of families with familial combined hyperlipidemia and their normolipidemia first-line relatives and to compare them with healthy individuals. The study includes non-smoking members of the affected families (probands and first-line relatives), who have not suffered from clinical manifestations of arteriosclerosis and/or hypertension during the start of the study. The cohort was divided into hyperlipidemic individuals (N = 25) and normolipidemic individuals (N = 21). Both groups were compared with control groups of healthy individuals (two groups, N = 17 each), who were adjusted by age and sex. The following markers of endothelial dysfunction were examined: 1. ultrasound--flow mediated dilatation of brachial artery and 2. humoral--serum levels of von Willebrand factor, inhibitor of activator of plasminogen-1 and vasoadhesive molecules (vascular cell adhesion molecule-1, intercellular adhesion molecule-1). The members of families with familial combined hyperlipidemia displayed symptoms of endothelial dysfunction. In comparison with healthy controls the endothelial dysfunction was more expressed in hyperlipidemic individuals. They displayed a significantly lower flow-mediated dilatation of brachial artery (3.6 +/- 3.3% versus 6.6 +/- 2.8%, P < 0.01), higher levels of von Willebrand factor (152.8% +/- 79.1% versus 110.4% +/- 24.8%, P < 0.05), inhibitor of activator of plasminogen-1 (94.6 +/- 30.8 ng/ml versus 60.4 +/- 38.0 ng/ml, P < 0.01) and vasoadhesive molecules: vascular cell adhesion molecule-1 (927.0 +/- 167.7 ng/ml versus 814.7 +/- 171.1 ng/ml, P < 0.05), intercellular adhesion molecule-1 (601.7 +/- 89.5 ng/ml versus 544.8 +/- 59.8 ng/ml, P < 0.05). The normolipidemic individuals displayed only a significantly lower flow-mediated dilatation of brachial artery (5.6 +/- 2.6% versus 7.5 +/- 2.8%, P < 0.05) and higher levels of von Willebrand factor (136.8 +/- 40.32% versus 104.1 +/- 24.9%, P < 0.05). No significant difference was found in the levels of inhibitor of activator of plasminogen-1 and vasoadhesive molecules. The results indicated that members of families with familial combined hyperlipidemia represent a high-risk group from the standpoint of early manifestation of arteriosclerosis.
 ...
PMID:[Endothelial dysfunction in a family with familial combined hyperlipidemia]. 1451 86

The regulation of cerebrovascular permeability is critical for normal brain homeostasis, and the "breakdown" of the blood-brain barrier (BBB) is associated with the development of vasogenic edema and intracranial hypertension in a number of neurological disorders. In this study we demonstrate that an increase in endogenous tissue-type plasminogen activator (tPA) activity in the perivascular tissue following cerebral ischemia induces opening of the BBB via a mechanism that is independent of both plasminogen (Plg) and MMP-9. We also show that injection of tPA into the cerebrospinal fluid in the absence of ischemia results in a rapid dose-dependent increase in vascular permeability. This activity is not seen with urokinase-type Plg activator (uPA) but is induced in Plg-/- mice, confirming that the effect is Plg-independent. However, the activity is blocked by antibodies to the LDL receptor-related protein (LRP) and by the LRP antagonist, receptor-associated protein (RAP), suggesting a receptor-mediated process. Together these studies demonstrate that tPA is both necessary and sufficient to directly increase vascular permeability in the early stages of BBB opening, and suggest that this occurs through a receptor-mediated cell signaling event and not through generalized degradation of the vascular basement membrane.
 ...
PMID:Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. 1461 49

The aims of neurology in Japan in the 21st Century should include establishment of therapeutic measures for neurological diseases, training clinical neurologists to cover both static and dynamic aspects of neurology, and application of gene therapy and neurogenesis to clinical neurology. It is also important to note that once any neurological disease develops, remaining sequelae are usually not curable, so the problem of how to prevent the onset of neurological diseases, that is preventive neurology, will become increasingly important. The key target for prevention in neurology is cerebro-vascular disease, since it is very common. Many risk factors are known for ischemic CVD. However, even for the management of hypertension, the so-called number needed to treat (NNT) is 29-118/5 years for primary prevention and 14-23/5 years for secondary prevention. It is also important to consider genetic factors that influence CVD, including abnormal plasminogen, Lp (a), ACT Isehara 1 gene, apolipoprotein E and so on, since these congenital factors reinforce known acquired risk factors, such as hypertension. In addition, the presence of asymptomatic cerebral infarction, as well as PVH and DSWMH, in MRI T2-weighted images is an important predictor of future symptomatic CVD. Finally, storage of one's own bone marrow cells might be useful, since in the event of onset of CVD, dementia or other neurological diseases, autotransplantation with cytokine might become available for neurogenesis. The results of our recent experiments indicate that this idea may be feasible.
 ...
PMID:[Neurology in the 21st century--the era of preventive neurology utilizing new diagnostic and therapeutic techniques]. 1515 50

The importance of obtaining insight in the structure/function relationship in the serpin plasminogen activator inhibitor type-1 can be understood from the major role PAI-1 plays in different (patho)physiological processes, mainly because of its involvement in the plasminogen/plasmin system. Moreover, during the past years, studies indicated a contribution of PAI-1 to the development of cardiovascular disease in common syndromes such as atherosclerosis, diabetes and hypertension. Furthermore, PAI-1 also inhibits u-PA, attributing a role in phenomena such as cell migration and tissue remodelling. Considering the role of PAI-1 in such various pathogenic path-ways, detailed insight into the structure/function relationship in PAI-1 might provide a means of interfering with a given pathological situation without disturbing other physiological processes. Therefore, since the discovery of PAI-1 and the cloning of its cDNA 20 years ago, over 600 PAI-1 variants have been constructed, elucidating the most important structural features of PAI-1. This review gives an overview of the contribution of the different PAI-1 variants to the understanding of the structure/function relationship in PAI-1, based on the different functional features of PAI-1.
 ...
PMID:The story of the serpin plasminogen activator inhibitor 1: is there any need for another mutant? 1554 16

The risk of ischemic heart disease is 2-4 times greater in diabetes, occurs at a younger age, and is much higher in women with diabetes. The risk of coronary disease is increased in patients with poor glycemic control, but studies have not shown a major impact of improved glucose management on cardiovascular mortality. This apparent contradiction may be due to the many potential mechanisms of increased cardiovascular damage in diabetes, including hypertension; abnormal clotting function due to changes in fibrinolysis, platelet adherence, and plasminogen activity; abnormal vascular reactivity; and abnormal lipid patterns and particles. Some, but not all, of these issues are related to lifestyle factors, including diet, exercise, and cigarette smoking. The treatment of hypertension and hypercholesterolemia has been more successful in reducing cardiovascular mortality than reducing HbA1c levels. One of the major, unresolved questions is whether insulin resistance rather than hyperglycemia is the primary risk factor for cardiovascular disease (CVD). Antidiabetic agents that target insulin resistance may be more cardioprotective than those that primarily augment insulin secretion.
 ...
PMID:Advances in diabetes for the millennium: the heart and diabetes. 1564 12

Blood pressure (BP) measured at home early in the morning (HBP) has been recognized as a useful predictor for organ damage and has been viewed as an important therapeutic target in patients with hypertension. The present study was aimed to determine whether this notion holds true in patients with progressive renal disease. The study enrolled patients with mild to moderate renal impairment. They were all directed to record self-measured HBP to evaluate the adequacy of BP control. In addition to the conventional antihypertensive therapy, intensive treatment to more efficiently reduce elevated morning HBP was applied, especially in patients with diabetic nephropathy. The results were as follows: 1) The status of BP control assessed using HBP and office/clinic BP (OBP) shows predominance of morning hypertension. The prevalence of patients with well-controlled systolic HBP was 38%, those with poorly-controlled HBP 30%, masked hypertension 20% and white coat hypertension 12%. 2) Early morning systolic HBP in diabetics was significantly higher than that in non-diabetics. However, when evaluated on systolic OBP, both groups were comparable.3)Logistic regression analysis showed that the predictive variables to explain morning hypertension (more than 130 mmHg and increased systolic HBP) were age, amount of daily urinary protein excretion and left ventricular mass index (LVMI).4)Following conventional therapy, intensive antihypertensive therapy consisting of calcium channel blockers (CCB) and/or diuretics given in the morning, and angiotensin receptor blockers (ARB) given in the evening, together with alpha1-blockers given at bedtime, efficaciously reduced elevated HBP in the morning. This result was associated with significant reduction in daily urinary protein excretion and in serum plasminogen-activator inhibitor (PAI-1) concentration. The present study indicates that, regardless of ongoing conventional antihypertensive therapy, the majority of patients with renal disease had morning hypertension, suggesting that these patients are at a higher risk for cardiovascular disease. For the purpose of improving morning hypertension, intensive treatments with combined CCB, ARB and alpha1-blockers could have substantial benefit on the morbidity and prognosis in patients with diabetic nephropathy.
 ...
PMID:Morning blood pressure predicts hypertensive organ damage in patients with renal diseases: effect of intensive antihypertensive therapy in patients with diabetic nephropathy. 1641 38

Adipose tissue secretes bioactive peptides, termed 'adipokines', which act locally and distally through autocrine, paracrine and endocrine effects. In obesity, increased production of most adipokines impacts on multiple functions such as appetite and energy balance, immunity, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism and haemostasis, all of which are linked with cardiovascular disease. Enhanced activity of the tumour necrosis factor and interleukin 6 are involved in the development of obesity-related insulin resistance. Angiotensinogen has been implicated in hypertension and plasminogen activating inhibitor-1 (PAI-1) in impaired fibrinolysis. Other adipokines like adiponectin and leptin, at least in physiological concentrations, are insulin sparing as they stimulate beta oxidation of fatty acids in skeletal muscle. The role of resistin is less understood. It is implicated in insulin resistance in rats, but probably not in humans. Reducing adipose tissue mass, through weight loss in association with exercise, can lower TNF-alpha and IL-6 levels and increase adiponectin concentrations, whereas drugs such as thiazolinediones increase endogenous adiponectin production. In-depth understanding of the pathophysiology and molecular actions of adipokines may, in the coming years, lead to effective therapeutic strategies designed to protect against atherosclerosis in obese patients.
 ...
PMID:The endocrine function of adipose tissue: an update. 1658 5

Tissue accumulation of circulating prorenin results in angiotensin generation, but could also, through binding to the recently cloned (pro)renin receptor, lead to angiotensin-independent effects, like p42/p44 mitogen-activated protein kinase (MAPK) activation and plasminogen-activator inhibitor (PAI)-1 release. Here we investigated whether prorenin exerts angiotensin-independent effects in neonatal rat cardiomyocytes. Polyclonal antibodies detected the (pro)renin receptor in these cells. Prorenin affected neither p42/p44 MAPK nor PAI-1. PAI-1 release did occur during coincubation with angiotensinogen, suggesting that this effect is angiotensin mediated. Prorenin concentration-dependently activated p38 MAPK and simultaneously phosphorylated HSP27. The latter phosphorylation was blocked by the p38 MAPK inhibitor SB203580. Rat microarray gene (n=4800) transcription profiling of myocytes stimulated with prorenin detected 260 regulated genes (P<0.001 versus control), among which genes downstream of p38 MAPK and HSP27 involved in actin filament dynamics and (cis-)regulated genes confined in blood pressure and diabetes QTL regions, like Syntaxin-7, were overrepresented. Quantitative real-time RT-PCR of 7 selected genes (Opg, Timp1, Best5, Hsp27, pro-Anp, Col3a1, and Hk2) revealed temporal regulation, with peak levels occurring after 4 hours of prorenin exposure. This regulation was not altered in the presence of the renin inhibitor aliskiren or the angiotensin II type 1 receptor antagonist eprosartan. Finally, pilot 2D proteomic differential display experiments revealed actin cytoskeleton changes in cardiomyocytes after 48 hours of prorenin stimulation. In conclusion, prorenin exerts angiotensin-independent effects in cardiomyocytes. Prorenin-induced stimulation of the p38 MAPK/HSP27 pathway, resulting in alterations in actin filament dynamics, may underlie the severe cardiac hypertrophy that has been described previously in rats with hepatic prorenin overexpression.
Hypertension 2006 Oct
PMID:Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II. 1694 Feb 9


<< Previous 1 2 3 4 5 6 7 8 Next >>