Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the Streptozotocin-induced diabetic rat heart, a decrease in the conductivity and suppression of electrical cell-to-cell coupling were observed. To clarify this mechanism, the present study was performed to investigate alterations of the gap junction connexin 43 (Cx43) using immunoblotting, immunohistochemistry, electron-microscopic analyses. An enhanced activation of PKCepsilon, an augmentation of PKCepsilon-mediated phosphorylation of Cx43, a decrease in the total amount of Cx43, a reduction in the area of immunoreactive particles for Cx43 at the intercalated disk, distribution of Cx43 to cell periphery or cytoplasm and the internalization approximately annular profiles of the gap junction were all characteristically recognized in the diabetic heart. Such abnormalities in the expression of Cx43 were alleviated by treatment with either lysosomal (NH(4)Cl, Leupeptin) or proteasomal inhibitor (ALLN). These results suggest that the PKCepsilon-mediated hyperphosphorylation of Cx43 makes Cx43 vulnerable to proteolytic degradation and that a decrease in the conductivity in the diabetic heart is also caused by a decrease in the number of gap junction channels due to an acceleration of the proteolytic degradation of Cx43. The remodeling of Cx43 induced by the activation of PKCepsilon may therefore contribute to the formation of the arrhythmogenic substrate in the diabetic heart. The cardioprotective effect of the remodeling of Cx43 by PKCepsilon is discussed.
Mol Cell Biochem 2006 Oct
PMID:Remodeling of connexin 43 in the diabetic rat heart. 1663 35

The study has been designed to investigate the effect of demethylasterroquinone B1 (DAQ B1), an activator of Akt, in diabetes mellitus (DM) and hyperhomocysteinemia (HHcy)-induced vascular endothelial dysfunction. Streptozotocin (55 mg kg(-1), i.v.) and methionine (1.7% w/w, p.o., 4 weeks) were administered to rats to produce DM (serum glucose >140 mg dl(-1)) and HHcy (serum homocysteine >10 microM), respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta and serum concentration of nitrite/nitrate. The expression of messenger RNA for p22phox and eNOS was assessed by reverse transcription-polymerase chain reaction. Serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide anion were estimated to assess oxidative stress. DAQ B1 (5 mg kg(-1), p.o.) or atorvastatin (30 mg kg(-1), p.o.) in diabetic and hyperhomocysteinemic rats significantly reduced serum glucose and homocysteine concentration. DAQ B1 or atorvastatin markedly improved acetylcholine-induced endothelium-dependent relaxation, vascular endothelial lining, serum nitrite/nitrate concentration and serum TBARS in diabetic and hyperhomocysteinemic rats. However, this ameliorative effect of DAQ B1 has been prevented by L-NAME (25 mg kg(-1), i.p.), an inhibitor of eNOS. Therefore, it may be concluded that DAQ B1-induced activation of Akt may activate eNOS and consequently reduce oxidative stress to improve vascular endothelial dysfunction.
Mol Cell Biochem 2007 Jan
PMID:Possible role of Akt to improve vascular endothelial dysfunction in diabetic and hyperhomocysteinemic rats. 1684 Nov 79

Both, diabetes mellitus (DM) and hypercholesterolemia (HCH) are known as risk factors of ischemic heart disease, however, the effects of experimental DM, as well as of HCH alone, on ischemia/reperfusion-induced myocardial injury are not unequivocal. We have previously demonstrated an enhanced resistance to ischemia-induced arrhythmias in rat hearts in the acute phase of DM. Our objectives were thus to extend our knowledge on how DM in combination with HCH, a model that is relevant to diabetic patients with altered lipid metabolism, may affect the size of myocardial infarction and susceptibility to arrhythmias. A combination of streptozotocin (STZ; 80 mg/kg, i.p.) and the fat-cholesterol diet (1% cholesterol, 1% coconut oil; FCHD) was used as a double-disease model mimicking DM and HCH simultaneosly occurring in humans. Following 5 days after STZ injection and FCHD leading to increased blood glucose and cholesterol levels, anesthetized open-chest diabetic, diabetic-hypercholesterolemic (DM-HCH) and age-matched control rats were subjected to 6-min ischemia (occlusion of LAD coronary artery) followed by 10 reperfusion to test susceptibility to ventricular arrhythmias in the in vivo experiments and to 30-min ischemia and subsequent 2-h reperfusion for the evaluation of the infarct size (IS) in the Langendorff-perfused hearts. The incidence of the most life-threatening ventricular arrhythmia, ventricular fibrillation, was significantly increased in the DM-HCH rats as compared with non-diabetic control animals (100% vs. 50%; p<0.05). Likewise, arrhythmia severity score (AS) was significantly higher in the DM-HCH rats than in the controls (4.9+/-0.2 vs. 3.5+/-0.5; p<0.05), but was not increased in the diabetic animals (AS 3.7+/-0.9; p>0.05 vs. controls). Diabetic hearts exhibited a reduced IS (15.1+/-3.0% of the area at risk vs. 37.6+/-2.8% in the control hearts; p<0.05), however, a combination of DM and HCH increased the size of myocardial infarction to that observed in the controls. In conclusion, HCH abrogates enhanced resistance to ischemia-reperfusion injury in the diabetic rat heart.
Mol Cell Biochem 2007 Jan
PMID:Hypercholesterolemia abrogates an increased resistance of diabetic rat hearts to ischemia-reperfusion injury. 1690 Mar 95

The objective was to describe the changes in catecholamine levels, noradrenaline (NA) release and the ultrastructural and immunohistochemical changes in the sympathetic nerves in the penis of STZ-diabetic rats. Amines were measured using HPLC. Nerves were studied using immunocytochemistry for tyrosine hydroxylase, and electron microscopy. Diabetic animals were compared with age-matched controls. The concentration of penile NA increases at least 2.5-fold after about 10 weeks of hyperglycaemia, is maintained for over 40 weeks. The rate of release of NA in the diabetics also increases approximately by fourfold. Immunohistochemical staining for tyrosine hydroxylase showed either no change or an increase in the levels of the enzyme around the central arteries and the outer coverings of the corpus cavernosum. Cavernosal nerves show increased intensity of staining for tyrosine hydroxylase, and the presence of dilated nerve fibres and engorged endings. The axons of the dorsal nerve of the diabetic penis have a smaller cross-sectional area that is most marked in unmyelinated axons. In the diabetic penis, the nerve endings appear to contain significantly more NA than the controls, and the turnover of noradrenaline is increased substantially. There is immunocytochemical evidence of an increase in staining for tyrosine hydroxylase, suggesting an increase in synthetic activity. These results are discussed in relation to the existing literature on the role of amines in normal and disordered erectile function. In particular, the increased concentration and turnover of NA in the diabetic rat contrasts with the fall in NA in cavernosal blood described during normal erection in humans.
Mol Cell Biochem 2007 Jan
PMID:The effects of age and streptozotocin diabetes on the sympathetic innervation in the rat penis. 1694 8

Attention was recently drawn to differences in the fatty acid pattern of liver phospholipids and triglycerides in animal models of type 1 and type 2 diabetes. The present study extends this knowledge to epididymal or parametrial adipose tissue lipids. The fatty acid pattern of such lipids was established in four fed female normal rats, four overnight fasted female normal rats, six fed female rats rendered diabetic by an injection of streptozotocin 3 days before sacrifice (STZ rats), and four female and four male Goto-Kakizaki rats (GK rats) also examined in the fed or fasted state. In addition to the fasting-induced and diabetes-related changes in plasma D-glucose and insulin concentrations, differences in either the weight percentage of fatty acids or the paired ratio between distinct fatty acids were often encountered. For instance, in the GK rats, gender differences were observed in the weight percentage of C18:2omega6, as well as C18:2omega6/C18:3omega6, C18:3omega6/C20:4omega6, C20:5omega3/C22:5omega3 and C22:5omega3/C22:6omega3 ratios. When compared to normal rats, the activity of Delta9-desaturase was markedly increased in GK rats and, to a lesser extent, in STZ rats. Starvation also increased to some extent the activity of Delta9-desaturase. The relative content of C22:6omega3 was also higher in diabetic than in normal rats. Further differences between GK and STZ rats concerned the generation of C18:3omega6 from C18:2omega6, C20:4omega6 from C18:3omega6, and C20:5omega3 from C18:3omega3. Several differences found in the adipose tissue of GK versus STZ rats were reminiscent of those recently identified in the liver triglycerides of these two types of diabetic animals, suggesting a common regulatory mechanism, possibly linked to the higher insulinemia of GK rats versus STZ rats.
Int J Mol Med 2006 Dec
PMID:Fatty acid content and pattern of epididymal and parametrial adipose tissue lipids in streptozotocin (type 1) and Goto-Kakizaki (type 2) diabetic rats. 1708 31

Flexibility in substrate selection is essential for the heart to maintain production of energy and contractile function, and is managed through multiple mechanisms including PPAR-alpha and AMP-activated protein kinase (AMPK). Rats injected with 55 mg/kg STZ (D55) were kept for 4 days (acute diabetes; D55-A) prior to termination. Fatty acid (FA) oxidation increased in D55-A hearts, with no significant change in gene expression of PPAR-alpha, or its downstream targets. However, both AMPK and ACC phosphorylation were significantly higher in these hearts, effects that were reversed by insulin. Unexpectedly, when the duration of diabetes in D55 rats was extended to 6 weeks (chronic diabetes; D55-C), AMPK and ACC phosphorylation were comparable in control and D55-C hearts. In D55-C rat hearts, lack of AMPK activation was closely associated to an overload of plasma and cardiac lipids. To validate the relationship between lipids and cardiac AMPK activation, we either induced more severe diabetes (100 mg/kg STZ to provoke both hyperglycemia and hyperlipidemia acutely; D100-A) or infused intralipid (IL) to enlarge circulating lipids. There was no difference in cardiac AMPK and ACC phosphorylation in D100-A rats compared to control. Measurement of AMPK and ACC phosphorylation in control and D55-A hearts revealed that their phosphorylation was inhibited by acute intralipid infusion. Our data suggest that activation of AMPK is an adaptation that would ensure adequate cardiac energy production when glucose utilization is compromised. However, in severe diabetes, with the addition of augmented plasma and heart lipids, AMPK activation is prevented, and control of FA oxidation is likely through alternate mechanisms. Given that AMPK plays an important role in preventing cardiac ischemic/reperfusion damage, it is possible that in these diabetic hearts, the accelerated damage observed during exposure to ischemia/reperfusion could be a likely outcome of a compromised activation of AMPK.
J Mol Cell Cardiol 2007 Feb
PMID:AMPK control of myocardial fatty acid metabolism fluctuates with the intensity of insulin-deficient diabetes. 1718 7

Many clinical trials have demonstrated that angiotensin converting enzyme inhibitors have protective effects on organ damage, suggesting the importance of inhibition of the renin-angiotensin system. In this study, we investigated the effects of a non-depressor dose of imidapril on organ damage induced by diabetes and hypertension. Diabetes was induced by an intravenous injection of streptozotocin (STZ, 40 mg/kg) in 15-week-old male spontaneously hypertensive rats (SHR). Imidapril (2 mg/kg/day) or vehicle was given orally for 28 days, and then the heart weight, left ventricle mass (LVM), urinary albumin excretion (UAE) and endothelial function were examined, as well as the urinary NOx level and local hepatocyte growth factor (HGF) expression. There were no significant differences between the treated groups in systolic blood pressure and plasma parameters. On the other hand, UAE was significantly suppressed in the imidapril-treated group (450+/-44 mg/day) compared to the vehicle-treated group (963+/-182 mg/day) (p<0.01). Moreover, endothelial function assessed by dilative reaction to acetylcholine as well as cardiac hypertrophy assessed by both heart/body weight ratio and LVM were significantly improved in the imidapril-treated group (p<0.05 and p<0.01, respectively). The urinary NOx concentration and local HGF expression in vessel walls were also significantly increased in the imidapril-treated group (p<0.01). A non-depressor dose of imidapril showed protective effects against organ damage in diabetic SHR, which may be partially due to the increase of HGF and NO.
Int J Mol Med 2007 Apr
PMID:Improvement of organ damage by a non-depressor dose of imidapril in diabetic spontaneously hypertensive rats. 1733 32

NHE1 is a ubiquitously expressed Na+/H+ exchanger, which is important for vital cell functions. Using in vivo models of kidney podocyte injury and renal tubular epithelial cell (RTC) culture systems, we previously demonstrated that NHE1 defends against apoptosis by a mechanism involving ezrin binding to the NHE1 cytoplasmic domain. We now extend the NHE1 role to diabetic mouse models and refine the mechanism of NHE1-dependent ezrin activation. Streptozotocin induced diabetes resulted in greater azotemia, albuminuria and tubulointerstitial pathology in NHE1-deficient swe/swe compared to wild-type control mice. Increased RTC apoptosis was noted in swe/swe mice, suggesting that loss of NHE1 function leads to tubular atrophy, which predicts kidney disease progression. In vitro, proximal RTC derived from swe/swe mice also underwent increased apoptosis in response to staurosporine or a hypertonic environment. Activated ezrin normally resides in the apical domain of the proximal RTC, while NHE1 is a basolateral protein. After NHE1 activation by intracellular acidification or extracellular hypertonicity, confocal immunofluorescence microscopy in polarized LLC-PK1 cells demonstrated transient ezrin localization to lateral membrane domains, where it is positioned to interact with NHE1. We conclude that cell stresses promote NHE1-ezrin interaction, which activate cell survival pathways to prevent apoptosis in diabetic and non-diabetic kidney diseases.
Cell Mol Biol (Noisy-le-grand) 2006 Dec 30
PMID:The NHE1 Na+/H+ exchanger regulates cell survival by activating and targeting ezrin to specific plasma membrane domains. 1753 45

Transduction with a liver specific, metabolically responsive insulin transgene produces near-normal blood sugars in STZ-diabetic rats. To overcome the limited duration of hepatic transgene expression induced by E1A-deleted adenoviral vectors, we evaluated recombinant adeno-associated virus (rAAV2) for cell type specificity and glucose responsiveness in vitro. Co-infection of AAV2 containing the glucose responsive, liver-specific (GlRE)(3)BP-1 promoter with an empty adenovirus enhanced transduction efficiency, and shortened the duration of transgene expression in HepG2 hepatoma cells, but not primary hepatocytes. However, in the context of rAAV2, (GlRE)(3)BP-1 promoter activity remained confined to cells of hepatocyte lineage, and retained glucose responsiveness. While isolated infection with an insulin expressing rAAV2 failed to attenuate blood sugars in diabetic mice, adenoviral co-administration with the same rAAV2 induced transient, near-normal random blood sugars in a diabetic animal. We conclude that rAAV2 can induce metabolically responsive insulin secretion from hepatocytes in vitro and in vivo. However, alternative AAV serotypes will likely be required to efficiently deliver therapeutic genes to the liver for the treatment of diabetes mellitus.
Mol Cell Endocrinol 2007 Jul 15
PMID:Adeno-associated viral delivery of a metabolically regulated insulin transgene to hepatocytes. 1755 15

Previous studies in isolated perfused heart and in atrial preparations have demonstrated significant reductions in beating rate in STZ-induced diabetic rats, which suggests that sinus arrhythmias in diabetes mellitus may be partly caused by intrinsic alteration of sino-atrial node (SAN) function. The effects of diabetes on electrical activity and expression levels of mRNA for gap junction proteins in the SAN have been investigated. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg) administered to young male Wistar rats (200-250 g). Experiments were performed 8-10 weeks after treatment. Conduction time and pacemaker cycle length were measured in sino-atrial node preparations with extracellular electrodes. Expression levels of mRNA for Gja5 (Cx40), Gja1 (Cx43) and Gja7 (Cx45) were measured in SAN and compared with right atrium and right ventricle with real-time quantitative reverse transcription-polymerase chain reaction. Diabetes was confirmed by a significant elevation of blood glucose (356+/-21 mg/dl) compared to age-matched controls (66+/-2 mg/dl). Pacemaker cycle length was significantly prolonged in diabetic heart (415+/-43 ms, n=6) compared to controls (255+/-7 ms, n=6). Sino-atrial conduction time was also significantly prolonged in diabetic hearts (12+/-2 ms) compared to controls (7+/-1 ms). Expression levels of mRNA for Gja5 (Cx40) and Gja1 (Cx43) were moderately increased and for Gja7 (Cx45) was significantly increased in SAN from diabetic heart compared to controls. Expression levels for gap junction connexin proteins were not significantly altered in right atrium or right ventricle from diabetic heart compared to controls. Structural remodelling of gap junction connexin proteins may partly underlie electrophysiological defects in STZ-induced diabetic rat SAN.
Mol Cell Biochem 2007 Nov
PMID:Altered expression of gap junction connexin proteins may partly underlie heart rhythm disturbances in the streptozotocin-induced diabetic rat heart. 1763 90


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