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

Tissue kallikrein, generally existing in living bodies as prokallikrein, is a serine proteinase that has proven of great significance to treat hypertension, cardiopathy and nephropathy. Although the extraction of tissue kallikrein from human urine is the most commonly used method to obtain such a protein, not only the yield is very little, but also the procedure is rather complex. Furthermore, the biological safety is uncertain. Therefore, the preparation of such a protein by genetic engineering method, including gene expression, cell culture, separation and purification, is very important. In this paper, a new method to obtain purified tissue prokallikrein excreted from insect cells by liquid chromatography has been proposed. In contrast to the previously published papers, the purification procedure is simplified to only three steps with the final yield of 57% and the purity of 95%, which is not only convenient, but also low-cost and suitable for the large-scale preparation of such a protein. The purified protein is further validated as prokallikrein by high performance liquid chromatography-mass spectrometry and amino acid sequencing.
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PMID:Purification of human tissue prokallikrein excreted from insect cells by liquid chromatography. 1604 95

The serine proteases of the trypsin superfamily are versatile enzymes involved in a variety of biological processes. In the cardiovascular system, the importance of these enzymes in blood coagulation, platelet activation, fibrinolysis, and thrombosis has been well established. Recent studies have shown that trypin-like serine proteases are also important in maintaining cardiac function and contribute to heart-related disease processes. In this review, we describe the biological function of corin, tissue kallikrein, chymase and urokinase and discuss their roles in cardiovascular diseases such as hypertension, cardiac hypertrophy, heart failure, and aneurysm.
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PMID:Serine proteases and cardiac function. 1605 20

With inhibition or absence of the bradykinin B2 receptor (B2R), B1R is upregulated and assumes some of the hemodynamic properties of B2R, indicating that both participate in the maintenance of normal vasoregulation or to development of hypertension. Herein we further evaluate the role of bradykinin in normal blood pressure (BP) regulation and its relationship with other vasoactive factors by selectively blocking its receptors. Six groups of Wistar rats were treated for 3 wk: one control group with vehicle alone, one with concurrent administration of B1R antagonist R-954 (70 microg x kg(-1) x day(-1)) and B2R antagonist HOE-140 (500 microg x kg(-1) x day(-1)), one with R-954 alone, one with HOE 140 alone, one with concurrent administration of both R-954 and HOE-140 plus the angiotensin antagonist losartan (5 mg x kg(-1) x day(-1)), and one with only losartan. BP was measured continuously by radiotelemetry. Only combined administration of B1R and B2R antagonists produced a significant BP increase from a baseline of 107-119 mmHg at end point, which could be partly prevented by losartan and was not associated with change in catecholamines, suggesting no involvement of the sympathoadrenal system. The impact of blockade of bradykinin on other vasoregulating systems was assessed by evaluating gene expression of different vasoactive factors. There was upregulation of the eNOS, AT1 receptor, PGE2 receptor, and tissue kallikrein genes in cardiac and renal tissues, more pronounced when both bradykinin receptors were blocked; significant downregulation of AT2 receptor gene in renal tissues only; and no consistent changes in B1R and B2R genes in either tissue. The results indicate that both B1R and B2R contribute to the maintenance of normal BP, but one can compensate for inhibition of the other, and the chronic inhibition of both leads to significant upregulation in the genes of related vasoactive systems.
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PMID:Role of bradykinin B1 and B2 receptors in normal blood pressure regulation. 1650 3

Tissue kallikrein (hK1) cleaves low-molecular-weight kininogen to produce kinin peptide, which binds to kinin receptors and triggers a wide spectrum of biological effects. Tissue kallikrein levels are reduced in humans and in animal models with hypertension, cardiovascular and renal diseases. Transgenic mice or rats over-expressing human tissue kallikrein or kinin B2 receptor are permanently hypotensive, and somatic kallikrein gene delivery reduces blood pressure in several hypertensive rat models. Moreover, kallikrein gene delivery or kallikrein protein infusion can directly improve cardiac, renal and neurological function without blood pressure reduction. Kallikrein has pleiotropic effects in inhibiting apoptosis, inflammation, proliferation, hypertrophy and fibrosis, and promoting angiogenesis and neurogenesis in different experimental animal models. Kallikrein's effects can be blocked by kinin B2 receptor antagonists. Mechanistically, tissue kallikrein/kinin leads to increased nitric oxide levels and Akt activation, and reduced reactive oxygen species formation, TGF-beta1 expression, MAPK and nuclear factor-kappaB activation. Our studies indicate that tissue kallikrein, through the kinin B2 receptor and nitric oxide formation, can protect against oxidative damage in cardiovascular and renal diseases and ischemic stroke. These novel findings suggest that kallikrein/kinin may serve as new drug targets for the prevention and treatment of heart failure, renal disease and stroke in humans.
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PMID:The tissue kallikrein-kinin system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reduction. 1680 Jul 27

We previously reported that iv delivery of the human tissue kallikrein (HK) gene reduced blood pressure and plasma insulin levels in fructose-induced hypertensive rats with insulin resistance. In the current study, we evaluated the potential of a recombinant adeno-associated viral vector expressing the HK cDNA (rAAV-HK) as a sole, long-term therapy to correct insulin resistance and prevent renal damage in streptozotocin-induced type-2 diabetic rats. Administration of streptozotocin in conjunction with a high-fat diet induced systemic hypertension, diabetes, and renal damage in rats. Delivery of rAAV-HK resulted in a long-term reduction in blood pressure, and fasting plasma insulin was significantly lower in the rAAV-HK group than in the control group. The expression of phosphatidylinositol 3-kinase p110 catalytic subunit and the levels of phosphorylation at residue Thr-308 of Akt, insulin receptor B, and AMP-activated protein kinases were significantly decreased in organs from diabetic animals. These changes were significantly attenuated after rAAV-mediated HK gene therapy. Moreover, rAAV-HK significantly decreased urinary microalbumin excretion, improved creatinine clearance, and increased urinary osmolarity. HK gene therapy also attenuated diabetic renal damage as assessed by histology. Together, these findings demonstrate that rAAV-HK delivery can efficiently attenuate hypertension, insulin resistance, and diabetic nephropathy in streptozotocin-induced diabetic rats.
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PMID:Tissue kallikrein reverses insulin resistance and attenuates nephropathy in diabetic rats by activation of phosphatidylinositol 3-kinase/protein kinase B and adenosine 5'-monophosphate-activated protein kinase signaling pathways. 1727 2

The pathogenesis of arterial hypertension often involves a rise in systemic vascular resistance (vasoconstriction and vascular remodeling) and impairment of salt excretion in the kidney (inappropriate salt retention despite elevated blood pressure). Experimental and clinical evidence implicate an imbalance between endogenous vasoconstrictor and vasodilator systems in the development and maintenance of hypertension. Kinins (bradykinin and lys-bradykinin) are endogenous vasodilators and natriuretic peptides known best for their ability to antagonize angiotensin-induced vasoconstriction and sodium retention. In humans, angiotensin-converting enzyme inhibitors, a potent class of antihypertensive agents, lower blood pressure at least partially by favoring enhanced kinin accumulation in plasma and target tissues. The beneficial actions of kinins in renal and cardiovascular disease are largely mediated by nitric oxide and prostaglandins, and extend beyond their recognized role in lowering blood pressure to include cardioprotection and nephroprotection. This article is a review of exciting, recently generated genetic, biochemical and clinical data from studies that have examined the importance of the tissue kallikrein-kinin system in protection from hypertension, vascular remodeling and renal fibrosis. Development of novel therapeutic approaches to bolster kinin activity in the vascular wall and in specific compartments in the kidney might be a highly effective strategy for the treatment of hypertension and its complications, including cardiac hypertrophy and renal failure.
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PMID:Mechanisms of disease: the tissue kallikrein-kinin system in hypertension and vascular remodeling. 1738 90

During the last few years the studies on the genetic basis of essential hypertension (EH) have been numerous, allowing however only a partial understanding of the underlying molecular mechanisms. The most used techniques were the candidate gene approach, genome-wide scanning, the intermediate phenotype approach and comparative-genomics in animal models. The renin-angiotensin-aldosterone system may play a prominent role in the genesis of hypertension, and polymorphisms of the genes coding for angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 and 2 receptors, and aldosterone synthase have been widely studied. Other mechanisms may involve the KLK 1 gene of tissue kallikrein, gene variants of endothelial nitric oxide synthase and polymorphisms of the endothelin-1 gene. Finally, a number of studies have highlighted the potential contribution of polymorphisms of genes coding for inflammatory cytokines, adrenergic receptors and intracellular G proteins, which can activate Na+/K+ exchangers. Further important information might derive from proteomic analysis and the study of mitochondrial genome. Overall, results have often been discordant, sometimes suggesting a different expression of the same gene variants in different populations. EH is a highly polygenic condition, caused by the combination of small changes in the expression of many genes, in conjunction with a variable collection of environmental factors.
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PMID:The genetic basis of essential hypertension. 1760 4

Somatic gene delivery approaches have received wide attention as a new technique for studying gene expression and as a potential therapeutic tool in treating both inherited and acquired diseases. Recent studies using nonviral and viral vectors have shown great promise for gene therapy in hypertensive diseases. Potential targets for prospective gene therapy in hypertension include vasopressor renin-angiotensin system components and a number of vasodilator polypeptides such as tissue kallikrein-kinin, atrial natriuretic peptide, adrenomedullin and nitric oxide synthase. Antisense inhibition with oligonucleotides or cDNAs encoding renin, angiotensinogen, angiotensin-converting enzyme and angiotensin receptors has been shown to cause a prolonged blood pressure reduction in spontaneously hypertensive rats. To evaluate the therapeutic potential of vasodilator proteins or peptides in high blood pressure, we delivered the genes encoding human tissue kallikrein, atrial natriuretic peptide, nitric oxide synthase, and adrenomedullin into hypertensive rat models and showed that a single injection resulted in a significant and sustained reduction of blood pressure for several weeks. The potency and duration of blood pressure reduction depends on the dose and the promoter of the gene administered, age and sex of the hypertensive animals as well as the vehicle used for gene delivery. Somatic gene transfer of human tissue kallikrein or atrial natriuretic peptide not only attenuated hypertension but also exerted a protective effect against salt-induced renal damage and cardiac hypertrophy in Dahl salt-sensitive rats after high salt loading. These results suggest that the application of antisense inhibition of vasopressors, or gene delivery of vasodepressors for gene therapy, may have potential in treating human hypertension, and cardiovascular and renal disorders.
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PMID:Gene therapy for hypertension: a review of potential targets. 1803 Nov 14

Recent evidence suggests a coordinated regulation by the local renin-angiotensin system (RAS) and tissue kallikrein-kinin system (TKKS) of blood flow and substrate supply in oxidative red myofibres of skeletal muscle tissue during endurance exercise. The performance of these myofibres is dependent on the increased oxidation of substrates facilitated by augmenting nutritive blood flow and glucose uptake. Humoral factors released by the contracting fibres, such as adenosine and kinins, are suggested to be responsible for this metabolic adjustment. The considerable drain of blood volume and the enormous consumption of glucose during endurance exercise require a control mechanism for the maintenance of blood pressure (BP) and glucose homeostasis. This is achieved by the sympathetic nervous system and its subordinate RAS, which is located in the nutritive vessels and parenchyma of the red myofibres. The angiotensin-converting enzyme (ACE) is the primary enzyme responsible for kinin degradation during exercise, underscoring the important interrelationship between the RAS and the TKKS in the critical role of kinins in the multifactorial regulation of muscle bioenergetics and glucose and BP homeostasis. Importantly, overactivity of the ACE, as occurs in individuals displaying risk factors such as overweight, causes exaggerated BP response and reduced glucose disposal. If they persist over years, compensatory responses to this ACE overactivity, such as hypersecretion of insulin and compliance of the vessel walls, will inevitably be exhausted, leading ultimately to the manifestation of type 2 diabetes and hypertension. This concept also provides a unifying explanation for the beneficial effects of ACE-inhibitors and Angiotensin II receptor antagonists in the treatment of hypertension and insulin resistance.
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PMID:Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis. 1858 83

Tissue kallikrein exerts various biological functions through kinin formation with subsequent kinin B2 receptor activation. Recent studies showed that tissue kallikrein directly activates kinin B2 receptor in cultured cells expressing human kinin B2 receptor. In the present study, we investigated the role of tissue kallikrein in protection against cardiac injury through direct kinin B2 receptor activation using kininogen-deficient Brown Norway Katholiek rats after acute myocardial infarction. Tissue kallikrein was injected locally into the myocardium of Brown Norway Katholiek rats after coronary artery ligation with and without coinjection of icatibant (a kinin B2 receptor antagonist) and N(omega)-nitro-L-arginine methylester (an NO synthase inhibitor). One day after myocardial infarction, tissue kallikrein treatment significantly improved cardiac contractility and reduced myocardial infarct size and left ventricle end diastolic pressure in Brown Norway Katholiek rats. Kallikrein attenuated ischemia-induced apoptosis and monocyte/macrophage accumulation in the ischemic myocardium in conjunction with increased NO levels and reduced myeloperoxidase activity. Icatibant and N(omega)-nitro-L-arginine methylester abolished kallikrein's effects, indicating a kinin B2 receptor NO-mediated event. Moreover, inactive kallikrein had no beneficial effects in cardiac function, myocardial infarction, apoptosis, or inflammatory cell infiltration after myocardial infarction. In primary cardiomyocytes derived from Brown Norway Katholiek rats under serum-free conditions, active, but not inactive, kallikrein reduced hypoxia/reoxygenation-induced apoptosis and caspase-3 activity, and the effects were mediated by kinin B2 receptor/nitric oxide formation. This is the first study to demonstrate that tissue kallikrein directly activates kinin B2 receptor in the absence of kininogen to reduce infarct size, apoptosis, and inflammation and improve cardiac performance of infarcted hearts.
Hypertension 2008 Oct
PMID:Tissue kallikrein elicits cardioprotection by direct kinin b2 receptor activation independent of kinin formation. 1876


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