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- Bulhak, A, et al.
(författare)
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Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation
- 2007
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Ingår i: American journal of physiology. Heart and circulatory physiology. - : American Physiological Society. - 0363-6135 .- 1522-1539. ; 292:6, s. H3158-H3163
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Tidskriftsartikel (refereegranskat)abstract
- Hydroxymethyl glutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) protect the myocardium against ischemia-reperfusion injury via a mechanism unrelated to cholesterol lowering. Statins may inhibit isoprenylation and thereby prevent activation of proteins such as RhoA. We hypothesized that statins protect the myocardium against ischemia-reperfusion injury via a mechanism involving inhibition of geranylgeranyl pyrophosphate synthesis and translocation of RhoA to the plasma membrane. Sprague-Dawley rats were given either the HMG-CoA reductase inhibitor rosuvastatin, geranylgeranyl pyrophosphate dissolved in methanol, the combination of rosuvastatin and geranylgeranyl pyrophosphate, rosuvastatin and methanol, or distilled water (control) by intraperitoneal injection for 48 h before ischemia-reperfusion. Animals were anesthetized and either subjected to 30 min of coronary artery occlusion followed by 2 h of reperfusion whereat infarct size was determined, or the expression of RhoA protein was determined in cytosolic and membrane fractions of nonischemic myocardium. There were no significant differences in hemodynamics between the control group and the other groups before ischemia or during ischemia and reperfusion. The infarct size was 80 ± 3% of the area at risk in the control group. Rosuvastatin reduced infarct size to 64 ± 2% ( P < 0.001 vs. control). Addition of geranylgeranyl pyrophosphate (77 ± 2%, P < 0.01 vs. rosuvastatin) but not methanol (65 ± 2%, not significant vs. rosuvastatin) abolished the cardioprotective effect of rosuvastatin. Geranylgeranyl pyrophosphate alone did not affect infarct size per se (84 ± 2%). Rosuvastatin increased the cytosol-to-membrane ratio of RhoA protein in the myocardium ( P < 0.05 vs. control). These changes were abolished by addition of geranylgeranyl pyrophosphate. We conclude that the cardioprotection and the increase of the RhoA cytosol-to-membrane ratio induced by rosuvastatin in vivo are blocked by geranylgeranyl pyrophosphate. The inhibition of geranylgeranyl pyrophosphate formation and subsequent modulation of cytosol/membrane-bound RhoA are of importance for the protective effect of statins against myocardial ischemia-reperfusion injury.
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- Bulhak, AA, et al.
(författare)
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PPAR-alpha activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway
- 2009
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Ingår i: American journal of physiology. Heart and circulatory physiology. - : American Physiological Society. - 0363-6135 .- 1522-1539. ; 296:3, s. H719-H727
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Tidskriftsartikel (refereegranskat)abstract
- Several clinical studies have shown the beneficial cardiovascular effects of fibrates in patients with diabetes and insulin resistance. The ligands of peroxisome proliferator-activated receptor-α (PPAR-α) reduce ischemia-reperfusion injury in nondiabetic animals. We hypothesized that the activation of PPAR-α would exert cardioprotection in type 2 diabetic Goto-Kakizaki (GK) rats, involving mechanisms related to nitric oxide (NO) production via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. GK rats and age-matched Wistar rats (n ≥ 7) were given either 1) the PPAR-α agonist WY-14643 (WY), 2) dimethyl sulfoxide (DMSO), 3) WY and the NO synthase inhibitor NG-nitro-l-arginine (l-NNA), 4) l-NNA, 5) WY and the PI3K inhibitor wortmannin, or 6) wortmannin alone intravenously before a 35-min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), expression of endothelial NO synthase (eNOS), inducible NO synthase, and Akt as well as nitrite/nitrate were determined. The IS was 75 ± 3% and 72 ± 4% of the area at risk in the Wistar and GK DMSO groups, respectively. WY reduced IS to 56 ± 3% in Wistar ( P < 0.05) and to 46 ± 5% in GK rats ( P < 0.001). The addition of either l-NNA or wortmannin reversed the cardioprotective effect of WY in both Wistar (IS, 70 ± 5% and 65 ± 5%, respectively) and GK (IS, 66 ± 4% and 64 ± 4%, P < 0.05, respectively) rats. The expression of eNOS and eNOS Ser1177 in the ischemic myocardium from both strains was increased after WY. The expression of Akt, Akt Ser473, and Akt Thr308 was also increased in the ischemic myocardium from GK rats following WY. Myocardial nitrite/nitrate levels were reduced in GK rats ( P < 0.05). The results suggest that PPAR-α activation protects the type 2 diabetic rat myocardium against ischemia-reperfusion injury via the activation of the PI3K/Akt and NO pathway.
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- Bulhak, A, et al.
(författare)
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Protection against myocardial ischaemia/reperfusion injury by PPAR-alpha activation is related to production of nitric oxide and endothelin-1
- 2006
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Ingår i: Basic Research in Cardiology. - : Springer Science and Business Media LLC. - 0300-8428 .- 1435-1803. ; 101:3, s. 244-252
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Tidskriftsartikel (refereegranskat)abstract
- Background Ligands of peroxisome proliferator-activated receptor alpha (PPAR-alpha) have been shown to reduce ischaemia/reperfusion injury. The mechanisms behind this effect are not well known. We hypothesized that activation of PPAR-alpha exerts cardioprotection via a mechanism related to nitric oxide (NO) and endothelin-1 (ET-1). Methods Five groups of anaesthetized open-chest Sprague-Dawley rats were given the PPAR-alpha agonist WY 14643 1 mg/kg (WY; n = 7), dimethyl sulfoxide (DMSO, vehicle for WY; n = 6), the combination of WY and the NO synthase inhibitor N-nitro-L-arginine (L-NNA, 2 mg/kg) (n = 7), L-NNA only (n = 8) or 0.9% sodium chloride (NaCl, vehicle for DMSO and L-NNA; n = 8) i.v. before a 30 min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), eNOS and iNOS protein and ET-1 mRNA expression were determined. Results There were no haemodynamic differences between the groups during the experiment. The IS was 78 +/- 3% of the area at risk in the DMSO group and 77 +/- 2% in the NaCl group (P = NS). WY reduced IS to 56 +/- 3% (P < 0.001 vs. DMSO group). When WY was administered in combination with L-NNA the cardioprotective effect was abolished (IS 73 +/- 3%, P < 0.01 vs. WY 14643). L-NNA did not affect IS per se (78 +/- 2%, P = NS). The expression of eNOS but not iNOS protein in ischaemic myocardium from rats was increased in the group given WY (P < 0.05). ET-1 mRNA levels were lower in the ischaemic myocardium following WY administration. Conclusion The results suggest that the PPAR-alpha activation protects the rat myocardium against ischaemia/ reperfusion injury via a mechanism related to production of NO, and possibly ET-1.
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- Rafik Hamad, Rangeen, et al.
(författare)
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Assessment of left ventricular structure and function in preeclampsia by echocardiography and cardiovascular biomarkers
- 2009
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Ingår i: Journal of Hypertension. - 0263-6352 .- 1473-5598. ; 27:11, s. 2257-2264
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To assess left ventricular (LV) structure and function in preeclampsia, a serious vascular-related pregnancy disorder, by Doppler tissue imaging (DTI) in combination with the levels of cardiovascular biomarkers. MATERIAL AND METHODS: Thirty-five pregnant women with preeclampsia and 30 with normal pregnancy, matched for age and gestational age were examined during pregnancy and 3-6 months after delivery. Transthoracic echocardiography and DTI were performed and blood levels of amino-terminal pro-brain natriuretic peptide (NT-pro-BNP), C-reactive protein (CRP), cystatin C and troponin I were analyzed. RESULTS: There were significant differences in LV and left atrial dimensions and function between the groups. A higher septal and lateral E/E' ratio (E = early transmitral diastolic flow velocity and E' = early diastolic myocardial velocity) (P < 0.0001, 0.0008) and higher levels of NT-pro-BNP, cystatin C, and lower cystatin C estimated GFR in ml/min per 1.73 m (P < 0.0001) were seen in the preeclampsia both during pregnancy and at follow-up. In addition the levels of E/E' ratio lateral and NT-pro-BNP were higher in pregnant women with early-onset preeclampsia necessitating delivery before 34 weeks of gestation than those who developed preeclampsia and delivered at or after 34 weeks (P = 0.0004, 0.005). CONCLUSION: In pregnancies complicated by preeclampsia, especially early-onset preeclampsia, the diastolic LV function is impaired and levels of biomarkers, NT-pro-BNP and cystatin C, are increased in comparison to normal pregnancy.
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- Settergren, M, et al.
(författare)
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Endothelin-A receptor blockade increases nutritive skin capillary circulation in patients with type 2 diabetes and microangiopathy
- 2008
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Ingår i: Journal of vascular research. - : S. Karger AG. - 1423-0135 .- 1018-1172. ; 45:4, s. 295-302
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Tidskriftsartikel (refereegranskat)abstract
- <i>Aims:</i> Endothelin-1 levels are elevated in patients with type 2 diabetes mellitus and may contribute to impaired microvascular function. We investigated the effect of selective endothelin-A (ET<sub>A</sub>) receptor blockade (BQ123) on skin microcirculation in patients with type 2 diabetes and albuminuria. <i>Methods:</i> Ten type 2 diabetes patients and 8 non-diabetic controls were investigated. Nutritive skin capillary circulation, investigated by videophotometric capillaroscopy, and total skin microcirculation, assessed by laser Doppler fluxmetry (LDF), were studied during intra-arterial infusion of saline for 15 min, followed by BQ123 infusion for 60 min. <i>Results:</i> Following BQ123 infusion there was a significant increase in resting capillary blood cell velocity (CBV) in patients with type 2 diabetes from 0.24 (0.20–0.34) mm/s at baseline to 0.61 (0.46–0.88) mm/s at 60 min, but no significant change in the control subjects [0.55 (0.10–0.68) vs. 0.38 (0.13–0.88) mm/s; p < 0.005 for difference between groups]. Peak CBV following arterial occlusion and skin temperature increased significantly in the type 2 diabetes group but not in the control group during BQ123 infusion. There were no significant changes in LDF parameters during infusion of BQ123 in either group. <i>Conclusion:</i> ET<sub>A</sub> receptor blockade improves nutritive skin capillary circulation in patients with type 2 diabetes and microangiopathy.
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