Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes mellitus is a major cause of ischemic coronary artery disease. Endothelial dysfunction is implicated in the pathogenesis of diabetic vascular disease. To examine coronary blood flow (CBF) regulation with endothelium-derived nitric oxide (EDNO) in the diabetic state, we compared the effects of both acetylcholine (ACh) and adenosine (Ado) on left circumflex coronary artery (LCX) blood flow in 12 vehicle-treated and 21 dogs made diabetic with alloxan anesthetized with pentobarbital. All dogs were pretreated with aspirin to inhibit endogenous prostaglandins. None of the hemodynamic parameters were significantly different in the two groups. The percent change in coronary vascular resistance (CVR) after ACh (100 ng/kg) infusion was significantly attenuated in diabetic dogs (-56.5 +/- 1.4%) as compared with vehicle-treated dogs (-64.5 +/- 1.2%) (p < 0.01), whereas the effect of Ado (1 microgram/kg) was not different between the two groups (-71.1 +/- 1.5% in vehicle, -67.0 +/- 1.3% in diabetes). After infusion of incremental doses of NG-nitro-L-arginine methyl ester (L-NAME) 10(-5)-10(-3)M, the effect of ACh was progressively inhibited in both groups and was different no longer between the two groups after the maximal dose. L-Arginine (L-ARG), but not D-ARG, significantly restored the effect of ACh in diabetic dogs but did not affect vehicle-treated dogs. The effect of Ado did not change after L- and D-ARG administration. Cu, Zn-superoxide dismutase (Cu, Zn-SOD) had no effect on any of the effects of ACh and Ado in diabetic dogs. Regulation of CBF with EDNO is impaired in dogs with alloxan-induced diabetes, and this impairment is partially restored by L-ARG.
J Cardiovasc Pharmacol 1996 Jul
PMID:Impairment of coronary blood flow regulation by endothelium-derived nitric oxide in dogs with alloxan-induced diabetes. 879 37

We studied the influence of dietary L-arginine (L-ARG) supplementation on forearm resistance arteries in vivo and the effect of exogenous addition of L-ARG to subcutaneous arteries isolated from gluteal biopsies. Twenty-six healthy males were recruited, and 16 were randomly allocated in a double-blind protocol to receive either oral L-ARG 20 g/day or placebo for 28 days. We examined responses to acetylcholine (ACh), sodium nitroprusside (SNP) and NG-monomethyl-L-arginine (L-NMMA) on forearm resistance arteries using venous occlusion plethysmography performed before and after supplementation of L-ARG (or placebo). L-ARG 20 g/day had no effect on plasma L-ARG levels (% mol based on total amino acid pool; before vs. after L-ARG 3.43 +/- 0.31 vs. 3.76 +/- 0.05), weekly blood pressure (BP) measurements, or plasma biochemical analysis of liver function enzymes, urea, or electrolyte levels. On the other hand, analysis of the major amino acids in plasma showed a significant difference in profile after L-ARG, but not placebo supplementation (Mann Whitney U test, p < 0.05), indicating a domino effect of chronic oral L-ARG supplementation on other amino acids. This may result from a change in appetite and thus protein intake after L-ARG supplementation. At the dose given, neither L-ARG nor placebo had any effect on forearm blood flow (FBF) responses to ACh (area under the dose-response curve, before vs. after L-ARG 1,763 +/- 260.1 vs. 1,862.8 +/- 163.6 U, Student's paired t test; p > 0.05), SNP, or L-NMMA. Gluteal skin biopsies were performed on 10 different untreated subjects. Subcutaneous arteries were isolated and mounted as ring preparations in isometric small vessel myographs. Full concentration-response curves to norepinephrine (NE), ACh, substance P, and a single response to SNP (10 microM) were obtained with and without addition of either L- or D-ARG 10 microM. Both L-ARG [-log EC50 (M) before vs. after arginine 7.12 +/- 0.15 vs. 6.66 +/- 0.16, Student's paired t test, p < 0.005] and D-ARG [-log EC50 (M) before vs. after arginine 7.36 +/- 0.17 vs. 6.85 +/- 0.18; Student's paired t test, p < 0.05] significantly antagonized responses to NE in subcutaneous arteries isolated from healthy humans. With the exception of a subset of vessels in which some endothelial dysfunction was observed, neither of the isomers of arginine had any effect on the responses to ACh, substance P, or SNP. In the subset vessels already described (n = 5), in which responses to ACh were < 90% maximal dilatation, L- but not D-ARG significantly increased the potency to ACh [-log EC50 (M) before vs. after L-ARG 7.42 +/- 0.20 vs. 8.27 +/- 0.28. Student's paired t test, p < 0.05]. We conclude that oral supplementation with L-ARG 20 g/day for 28 days does not affect endothelial function in normal healthy adults, possibly because the dose given in the current study was inadequate or because chronic oral administration leads to dissipation of arginine to other pathways, as evidenced by the change in total amino acid profile but not L-ARG plasma concentration, or because L-ARG cannot improve normal endothelium-mediated vasodilatation. These concepts are supported by our findings that responses to ACh and substance P were not altered by L-ARG in subcutaneous arteries isolated from healthy subjects.
J Cardiovasc Pharmacol 1996 Jul
PMID:Effects of in vivo and in vitro L-arginine supplementation on healthy human vessels. 879 50

We investigated the mechanism of action of gemfibrozil on high-density lipoproteins (HDL) and apolipoprotein (apo) A-I metabolism and atherogenesis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia and HDL deficiency. Two-month-old WHHL rabbits were fed either a normal control diet or a diet containing 0.5% gemfibrozil for 12 months. In vivo apo A-I kinetics, the fractional rate of cholesterol esterification in HDL (FER[HDL]), which reflects the reactivity of HDL to lecithin:cholesterol acyltransferase, and a morphometrical analysis of atherosclerotic lesions in the descending thoracic aorta, were examined. At 12 months, the mean levels of serum total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) in both groups had decreased to approximately 53%, 57%, and 87% of the initial levels (at 0 month), respectively, which is characteristic of homozygous WHHL rabbits of the physiologic influence of aging, and no differences in the levels of serum LDL-C, HDL-C, and triglycerides were found between the two groups. Rabbits treated with gemfibrozil exhibited a decreased FER(HDL) (38% of the controls, P = 0.039). Gemfibrozil induced a significant increase in the total mass of apo A-I (1.7-fold, P < 0.05) and in the rate of apo A-I synthesis (1.6-fold, P < 0.05). The atherosclerotic intimal area was positively correlated with serum LDL-C (P = 0.02) in both groups, but gemfibrozil did not affect the atherosclerotic intimal area. These results indicate that 12 months of treatment with gemfibrozil did not protect against atherosclerosis despite a significant increase in apo A-I synthesis and enhanced HDL function through FER(HDL). It is possible that both the qualitative and quantitative improvement in HDL by gemfibrozil cannot overcome the massive and long-term exposure of the vascular wall to LDL in these animals.
Cardiovasc Drugs Ther 1997 Nov
PMID:Mechanism of action of gemfibrozil on HDL metabolism and atherosclerosis in WHHL rabbits. 949 5

Rotationangioplasty and catheter atherectomy using the TEC device was performed in 33 patients with peripheral arterial occlusive disease. Thirty-five femoral or popliteal artery occlusions could be recanalized with an initial patency of 100%. After 5 years the patients were re-evaluated by clinical examination, colour duplex scanning and in 5 cases by intra-arterial angiography. According to life table analysis there was no patent femoral or popliteal vessel after 5 years in those patients treated initially for rest pain or ischemic tissue loss. 82% of those treated for claudication had a re-occluded artery. In 5 cases a major amputation was necessary. 42% of those patients who were initially treated far disabling claudication had a severe deterioration of their functional status with development of critical ischemia. In 9 of these cases reconstructive arterial surgery was required which failed in one patient with subsequent limb loss. In the retrospective study presented patients with occlusions up to 30 cm and more were treated. Combining two interventional techniques there is a high initial success rate with poor long term results. Therefore these devices should be reserved for high risk patients who would not tolerate reconstructive vascular surgery. They should not be used in patients with claudication although even extensive occlusions can be recanalized there is an imminent danger of causing significant deterioration of the patients functional status.
J Cardiovasc Surg (Torino) 1998 Feb
PMID:Long term results after rotation angioplasty and catheter atherectomy. A retrospective analysis. 953 29

An 82-year-old woman undergoing percutaneous transluminal coronary angioplasty experienced perforation of the terminal portion of the left anterior descending coronary artery caused by guidewire trauma. The coronary artery perforation was successfully closed using a vascular occlusion system consisting of individual thrombogenic coils delivered to the site. Coronary artery perforation (CAP) during percutaneous transluminal coronary angioplasty (PTCA) has been reported to occur in less than 1% of cases. The incidence seems to be higher with the new interventional devices, e.g., DCA, TEC, and laser CAP may result in pericardial hemorrhage and cardiac tamponade or a coronary artery fistula to either the left or right ventricle. The management of CAP may include prolonged balloon inflations, reversal of anticoagulation, pericardiocentesis, and emergency surgery. Proximal perforations sometimes can be managed with vein covered stents. We describe another option in the treatment of distal CAP using a vascular occlusion system.
Cathet Cardiovasc Diagn 1998 Apr
PMID:Coronary artery perforation repair using microcoil embolization. 955 85

The central role of vascular endothelial growth factor (VEGF) in angiogenesis in health and disease makes it attractive both as a therapeutic target for anti-angiogenic drugs and as a pro-angiogenic cytokine for the treatment of ischaemic heart disease. While VEGF binds to two receptor protein tyrosine kinases, VEGFR1 (Flt-1) and VEGFR2 (KDR), most biological functions of VEGF are mediated via VEGFR2, and the role of VEGFR1 is currently unknown. Neuropilin-1, a non-tyrosine kinase transmembrane molecule, may function as a co-receptor for VEGFR2. Considerable progress has recently been made towards delineating the signal transduction pathways distal to activation of VEGFR2. Activation of the mitogen-activated protein kinase, protein kinase C and Akt pathways are all strongly implicated in mediating diverse cellular biological functions of VEGF, including cell survival, proliferation, the generation of nitric oxide and prostacyclin and angiogenesis. Upregulation of metalloproteinases, activation of focal adhesion kinase and interactions between VEGF receptors and integrins are strongly implicated in VEGF-induced endothelial cell migration. Recent findings suggest important roles for the vasodilators nitric oxide and prostacyclin, in linking post-receptor signaling networks to downstream biological effects and in mediating some in vivo endothelial functions of VEGF.
Cardiovasc Res 2001 Feb 16
PMID:Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. 1116 70

G(12) heterotrimeric G proteins transduce signals from a number of receptors involved in the regulation of cardiovascular function. Recently, it has been discovered that these G proteins regulate the activity of Bruton's tyrosine kinase and Ras-GAP1(m) through a conserved PH-BM domain. These findings provide new insights into the signaling pathways initiated by G(12), which regulate cytoskeletal organization, cell proliferation and cardiovascular function.
Trends Cardiovasc Med 2000 May
PMID:Signaling of G(alpha)(12) family of G proteins through a tyrosine kinase and a Ras-GAP. 1123 96

Integrins, major adhesion receptors and angiotensin II activate extracellular signal-regulated kinase (ERK) pathways and result in a mitogenic response such as the proliferation of vascular smooth muscle cells (VSMCs). We investigated mechanisms of collaboration or synergism between integrins and angiotensin II involving ERK pathways in VSMCs. Integrin activation by cell adhesion to fibronectin increased the phosphorylation level of focal adhesion kinase (FAK) upstream of the ERK pathway. angiotensin II induced a high increase in the phosphorylation level of FAK with integrin activation, but not in suspended cells. Integrin activation increased phosphorylation levels of ERK kinase (MEK) and ERK phosphorylation as well. Angiotensin II-induced MEK and ERK phosphorylation were retained even in suspended cells. Furthermore, with integrin activation, angiotensin II induced a much larger increase in the phosphorylation levels of MEK and ERK. These results suggest that simultaneous stimulation of integrin and angiotensin II receptors cause synergistic interaction in the activation of ERK pathway, possibly via phosphorylation of FAK, which may play a critical role in angiotensin II-mediated mitogenic response in VSMCs.
J Cardiovasc Pharmacol 2001 Oct
PMID:Synergistic interaction of integrin and angiotensin II in activation of extracellular signal-regulated kinase pathways in vascular smooth muscle cells. 1181 61

We report the first clinical experience in eight patients with a new stent and delivery system specifically designed for the treatment of bifurcational lesions. The device (AST SLK-View system) consists of a premounted stent and a delivery system. The stent has a side aperture, which orients toward the ostium of the side branch. The system allows deployment of the stent while the access to both main and side branches is maintained by two wires. We evaluated this system in nine bifurcations. The location of bifurcations was left descending artery/diagonal branch in four lesions, left circumflex/obtuse marginal branch in three lesions, and postero-lateral branch/posterior descending artery in two lesions. Predilation was performed in six lesions of the main branches and in five lesions of the side branches. The stent was effectively delivered to all bifurcations except for one, in which the target lesion was located at a distal segment and the device could not be delivered. Following stent implantation in the main branch, two lesions at the side branches were treated by stent, while the other lesions were treated by balloon angioplasty without difficulty. Final kissing balloon was performed in four bifurcation lesions. No adverse event was observed during 1 month of clinical follow-up. Treatment of bifurcation lesions with this new dedicated device appears to be feasible. This new device may introduce a new approach for the treatment of coronary bifurcation lesions.
Catheter Cardiovasc Interv 2003 Jan
PMID:A new dedicated stent and delivery system for the treatment of bifurcation lesions: preliminary experience. 1250 94

The Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway is a stress-responsive mechanism that transduces signals from the cell surface to the nucleus, thereby modulating gene expression. Recent studies have demonstrated that myocardial ischemia and reperfusion induce rapid activation of this pathway. Although the functional consequences of this event remain to be elucidated, there is emerging evidence that JAK-STAT signaling plays an important role in the development of the cardioprotected phenotype associated with ischemic preconditioning. Specifically, brief episodes of myocardial ischemia/reperfusion activate JAK1 and JAK2, followed by recruitment of STAT1 and STAT3, resulting in transcriptional upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), which then mediate the infarct-sparing effects of the late phase of preconditioning. The present review focuses on this novel cardioprotective role of JAK-STAT signaling and on its potential exploitation for developing therapeutic strategies aimed at limiting ischemia/reperfusion injury.
Trends Cardiovasc Med 2003 Feb
PMID:Role of the JAK-STAT pathway in protection against myocardial ischemia/reperfusion injury. 1258 43


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