No abstract

No abstract

No abstract

Diabetic cardiomyopathy is associated with increased oxidative stress and vascular endothelial dysfunction, which lead to coronary microangiopathy. We tested whether statin-induced redox imbalance improvements could ameliorate diabetic cardiomyopathy and improve coronary microvasculature in streptozotocin-induced diabetes mellitus (DM). Fluvastatin (10 mg/kg/day) or vehicle was orally administered for 12 weeks to rats with or without DM. Myocardial oxidative stress was assessed by NADPH (nicotinamide adenine dinucleotide phosphate) oxidase subunit p22(phox) and gp91(phox) mRNA expression, and myocardial 8-iso-prostaglandin F(2α) (PGF(2α)) levels. Myocardial vascular densities were assessed using anti-CD31 and anti-α-smooth muscle actin (SMA) antibodies. Fluvastatin did not affect blood pressure or plasma cholesterol, but attenuated increased left ventricular (LV) minimum pressure and ameliorated LV systolic dysfunction in DM rats in comparison with vehicle (LV dP/dt, 8.9 ± 1.8 vs 5.4 ± 1.0 × 10(3) mmHg/s, P < 0.05). Myocardial oxidative stress increased in DM, but fluvastatin significantly reduced p22(phox) and gp91(phox) mRNA expression and myocardial PGF(2α) levels. Fluvastatin enhanced myocardial endothelial nitric oxide synthase (eNOS) protein levels and increased eNOS, vascular endothelial growth factor, and hypoxia-inducible factor-1α mRNA expression. CD31-positive cell densities were lower in DM rats than in non-DM rats (28.4 ± 13.2 vs 48.6 ± 4.3/field, P < 0.05) and fluvastatin restored the number (57.8 ± 18.3/field), although there were no significant differences in SMA-positive cell densities between groups. Fluvastatin did not affect cardiac function, oxidative stress, or vessel densities in non-DM rats. These results suggest that beneficial effects of fluvastatin on diabetic cardiomyopathy might result, at least in part, from improving coronary microvasculature through reduction in myocardial oxidative stress and upregulation of angiogenic factor.

Danon disease is an X-linked dominant multisystem disorder that includes hypertrophic cardiomyopathy with skeletal myopathy, and results from mutations in the gene encoding the lysosome-associated membrane protein-2 (LAMP-2). To date, over 20 different mutations in LAMP2 have been identified. Three members of a family, a male proband (18 years old) and 2 sisters (15 and 20 years old) were studied. Their mother had been diagnosed with dilated cardiomyopathy at the age of 39 years, and died from advanced heart failure at the age of 43 years. The proband developed marked concentric hypertrophy at the age of 5 years and DNA analyses revealed a novel hemizygous frameshift mutation (c.573delA) in exon 5. The 2 affected sisters were also heterozygous for the same mutation. Functional analyses of this novel LAMP2 mutation are mandatory.

arly reperfusion of an occluded coronary artery preserves myocardial viability and function by limiting the size of the myocardial infarct. 1,2 However, despite early reperfusion, myocardial ischemia-reperfusion (IR) injuries, including no reflow, stunning and reperfusion arrhythmias, sometimes occur, thereby attenuating the cardioprotective effect of reperfusion therapy. 3 Recent studies in experimental animals have demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) attenuate IR injury independently of their lipid-lowering action. [4][5][6][7][8] Statins have pleiotropic effects, including improvement of endothelial function by increased nitric oxide (NO) bioavailability, 9 and antioxidant 10 and antiinflammatory actions, 11 which may explain their attenuation of IR injury. The experimental result of cardioprotection by statins has therapeutic implication for patients with acute coronary syndrome who will be treated with reperfusion therapy; however, the time at which statin treatment was administered before IR varied from hours to days, and the Circulation Journal Vol.70, December 2006 results are conflicting. 5,12 It is not clear whether acute administration of statins at the onset of ischemia or reperfusion will prevent or attenuate the IR injury.Oxidative stress plays an important role in IR injury, and antioxidants such as superoxide dismutase and catalase could limit the infarct size in IR. 13 Statins are known to decrease free radical generation in the vascular wall 14,15 and myocardium, 16 which suggests that statins may protect the ischemic myocardium from IR injury via suppression of oxygen-derived free radicals produced upon reperfusion. Among the statins, fluvastatin (FV) has a potent free radical scavenging property derived from its chemical structure 17 and the purpose of the present study was to elucidate the effects of acute administration of FV and the role of its antioxidant property on IR injury in rats. MethodsThe experimental procedures followed the approved guidelines for animal experimentation at the University of Toyama. Myocardial IRMale Wistar rats weighing 270-380 g (n=103) were intubated under ether anesthesia and ventilated using a rodent respirator. The heart was exposed by left thoracotomy and the left coronary artery was ligated 2-3 mm from its origin Background Three-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are known to attenuate myocardial ischemia-reperfusion (IR) injury. Fluvastatin (FV) has a potent free radical scavenging action, but it is unclear whether the timing of FV administration could affect its cardioprotective effect or if the antioxidant property of FV might attenuate IR injury. Methods and Results IR was induced in rats by left coronary artery occlusion for 30 min followed by 24-h reperfusion. The rats were divided into 4 groups: oral FV group (10 mg/kg per day for 2 weeks before ischemia); iv, FV group (10 mg/kg) before ischemia; iv, FV group (10 mg/kg) before reperfusion; and control gr...

Repeated sauna therapy (ST) increases endothelial nitric oxide synthase (eNOS) activity and improves cardiac function in heart failure as well as peripheral blood flow in ischemic limbs. The present study investigates whether ST can increase coronary vascularity and thus attenuate cardiac remodeling after myocardial infarction (MI). We induced MI by ligating the left coronary artery of Wistar rats. The rats were placed in a far-infrared dry sauna at 41°C for 15 min and then at 34°C for 20 min once daily for 4 wk. Cardiac hemodynamic, histopathological, and gene analyses were performed. Despite the similar sizes of MI between the ST and non-ST groups (51.4 ± 0.3 vs. 51.1 ± 0.2%), ST reduced left ventricular (LV) end-diastolic (9.7 ± 0.4 vs. 10.7 ± 0.5 mm, P < 0.01) and end-systolic (8.6 ± 0.5 vs. 9.6 ± 0.6 mm, P < 0.01) dimensions and attenuated MI-induced increases in LV end-diastolic pressure. Cross-sectional areas of cardiomyocytes were smaller in ST rats and associated with a significant reduction in myocardial atrial natriuretic peptide mRNA levels. Vascular density was reduced in the noninfarcted myocardium of non-ST rats, and the density of cells positive for CD31 and for α-smooth muscle actin was decreased. These decreases were attenuated in ST rats compared with non-ST rats and associated with increases in myocardial eNOS and vascular endothelial growth factor mRNA levels. In conclusion, ST attenuates cardiac remodeling after MI, at least in part, through improving coronary vascularity in the noninfarcted myocardium. Repeated ST might serve as a novel noninvasive therapy for patients with MI.

t is generally accepted that excess levels of norepinephrine (NE) could lead to myocardial injury. [1][2][3][4] Prolonged myocardial ischemia causes a large amount of NE to be released from the sympathetic nerve terminals via non-exocytotic local metabolic mechanism independently of central sympathetic activation, and this excessive NE may promote myocardial injury. 5 Reperfusion following prolonged ischemia would prevent progression of ischemic cell necrosis, whereas reperfusion itself causes myocardial injury, the phenomenon known as reperfusion injury. [6][7][8][9][10] Increased interstitial concentration of NE during ischemia may be involved in the pathogenesis of reperfusion injury, because NE is a source of free radicals. [11][12][13] Previous studies have shown that auto-oxidation of NE results in the generation of highly reactive ·OH radicals. 12,13 Thus, the pathogenesis of catecholamine-induced myocardial injury in the setting of reperfusion following prolonged ischemia is multifactorial, but the relative role of this NE-derived free radical formation in increasing the size of the infarct after reperfusion remains unclear. Accordingly, we studied the effects of cardiac denervation on free radical formation and infarct size in rats with reperfusion following prolonged ischemia and compared them with those of -adrenoceptor blockade. Methods Experimental AnimalThe experimental procedures were approved by the guidelines for animal experimentation at Toyama Medical and Pharmaceutical University. A total of 48 male Wistar rats weighing 300-350 g were used for induction of myocardial ischemia as described previously. 14 Briefly, the rats were anesthetized with sodium pentobarbital (30 mg/kg, ip), and a left thoracotomy was performed to exteriorize the heart. The left coronary artery was ligated 2-3 mm from its origin with a suture of 5-0 prolene (Ethicon, Inc, Somerville, NJ, USA) for 30 min, and then the ligature was released.The animals were divided into 3 groups: control, phenol, and atenolol. The following protocols were performed: (i) determination of hemodynamics and infarct size (control = 8, phenol =6, atenolol =6), (ii) determination of interstitial NE concentrations during ischemia and reperfusion (control =7, phenol =4, atenolol =4), and (iii) electron paramagnetic resonance (EPR) study (control =6, phenol =7). One week before coronary ligation, regional cardiac denervation was performed by painting a solution of 10% phenol in ethanol on the left ventricular (LV) epicardium around the proximal region of the left coronary artery. 15 The 1-selective adrenoceptor blockade, atenolol (0.5 mg/kg), was Background Norepinephrine (NE)-derived free radicals may contribute to myocyte injury after ischemiareperfusion, so the influence of sympathetic denervation on myocardial ischemia -reperfusion injury was investigated in the present study. Methods and ResultsCardiac sympathetic denervation was produced in Wistar rats by a solution of 10% phenol 1 week before ischemia. Atenolol (0.5 mg/kg) was intravenously a...