Changes in fatty acid compositions of myocardial lipids in rats with heart failure following myocardial infarction

Changes in fatty acid composition of myocardial lipids were examined in rats with heart failure following myocardial infarction. Left ventricular systolic pressure (LVSP) was decreased and left ventricular end-diastolic pressure (LVEDP) was elevated 24 h, 1 and 12 weeks after left coronary artery ligation (CAL), suggesting the development of heart failure at these periods in this model. Hearts were isolated 24 h, 1 week and 12 weeks after the operation. Myocardial lipids in the infarcted scar tissue, non-infarcted remaining left ventricle including interseptum and right ventricle were separated into phospholipid (PL), triacylglycerol (TG), diacylglycerol (DAG) and free fatty acid (FFA) fractions. In the scar tissue PL content markedly decreased whereas TG, DAG and FFA contents increased 24 h after CAL. Despite a marked decrease in constituted fatty acids of PL fraction in the scar tissue the percentage of arachidonic acid in PL was elevated 12 weeks after CAL, suggesting that release of arachidonic acid during PL degradation was suppressed. In the non-infarcted viable left ventricle PL content remained unchanged throughout the experiment whereas TG, DAG and FFA contents were elevated 24 h after CAL. Despite no changes in PL and other lipid contents in the non-infarcted tissue the percentage of linoleic acid in PL was reduced and that of docosahexaenoic acid in PL was elevated 12 weeks after CAL. Our findings showed that myocardial lipid composition of the non-infarcted left ventricle was altered only in an early stage of the development of heart failure and fatty acid compositions of PL was exchanged in a late stage of the development of heart failure. The exchange may be related to cardiac dysfunction or myocardial remodelling in the rat with heart failure.     

Serum prolactin levels in rats following isoproterenol-induced myocardial infarction.

Circulating prolactin levels were monitored in nonarteriosclerotic, arteriosclerotic, and hormonally sterilized male and female Sprague-Dawley rats during the acute necrosis and repair phases of myocardial infarction induced by isoproterenol. Male rats are particularly prone to succumb to acute myocardial ischemia but reduction of androgen levels by neonatal sterilization improved survival considerably. Circulating prolactin levels are greatly increased, particularly in females, during acute myocardial ischemia. Since androgens suppress the hypothalamic center for prolactin release, prolactin levels were delayed and transitory in males. It is suggested that the superior survival of female rats may be related to their greater production of prolactin during acute stages of myocardial ischemia, which would dampen the tachycardia-inducing effects of the potent beta-adrenergic stimulating agent, isoproterenol.     

Cardiomyocytes undergo cells division following myocardial infarction is a spatially and temporally restricted event in rats

Dividing cardiomyocytes are observed in autopsied human hearts following recent myocardial infarction, however there is a lack of information in the literature on the division of these cells. In this study we used a rat model to investigate how and when adult mammalian cardiomyocytes proliferate by cell division after myocardial infarction. Myocardial infarction was induced in Wistar rats by ligation of the left coronary artery. The rats were sacrificed periodically up to 28 days following induced myocardial infarction, and the hearts subjected to microscopic investigation. Cardiomyocytes entering the cell cycle were assayed by observation of nuclear morphology and measuring expression of Ki-67, a proliferating cell marker. Ki-67 positive cardiomyocytes and dividing nuclei were observed initially after 1 day. After 2 days dividing cells gradually increased in number at the ischemic border zone, reaching a peak increase of 1.12% after 3 days, then gradually decreasing in number. Dividing nuclei increased at the ischemic border zone after 3 days, peaked by 0.14% at day 5, and then decreased. In contrast, Ki-67 positive cells and dividing nuclei were limited in number in the non-ischemic area throughout all experiments. In conclusion, mitogenic cardiomyocytes are present in the adult rat heart following myocardial infarction, but were spatially and temporally restricted.     

2型糖尿病大鼠的尿液代谢组学改变

目的 通过检测2型糖尿病大鼠尿液代谢谱的变化.探讨代谢组学在糖尿病研究中的应用.方法 SD大鼠高糖高脂饲料喂养6周后,腹腔注射链脲菌素(Streptozotocin,STZ)37 mg/kg建立2型糖尿病模型,动态检测空腹血糖(FBG)变化,检测甘油三酯(TC)、总胆固醇(TC)、游离脂肪酸(FFA)及胰岛素(INS)...     

The heterogeneity of islet autoantibodies and the progression of islet failure in type 1 diabetic patients

Type 1 diabetes mellitus is heterogeneous in many facets. The patients suffered from type 1 diabetes present several levels of islet function as well as variable number and type of islet-specific autoantibodies. This study was to investigate prevalence and heterogeneity of the islet autoantibodies and clinical phenotypes of type 1 diabetes mellitus; and also discussed the process of islet failure and its risk factors in Chinese type 1 diabetic patients. A total of 1,291 type 1 diabetic patients were enrolled in this study. Demographic information was collected. Laboratory tests including mixed-meal tolerance test, human leukocyte antigen alleles, hemoglobinA1c, lipids, thyroid function and islet autoantibodies were conducted. The frequency of islet-specific autoantibody in newly diagnosed T1DM patients (duration shorter than half year) was 73% in East China. According to binary logistic regressions, autoantibody positivity, longer duration and lower Body Mass Index were the risk factors of islet failure. As the disease developed, autoantibodies against glutamic acid decarboxylase declined as well as the other two autoantibodies against zinc transporter 8 and islet antigen 2. The decrease of autoantibodies was positively correlated with aggressive beta cell destruction. Autoantibodies can facilitate the identification of classic T1DM from other subtypes and predict the progression of islet failure. As there were obvious heterogeneity in autoantibodies and clinical manifestation in different phenotypes of the disease, we should take more factors into consideration when identifying type 1 diabetes mellitus.     

Polymorphism of the angiotensin I-converting enzyme gene in diabetic retinopathy patients and type 2 diabetes mellitus patients with myocardial infarction

The insertion/deletion polymorphism (I/D) of the angiotensin I-converting enzyme gene (ACE) was examined in type I diabetes mellitus patients (DM) with (n = 31), or without (n = 33) retinopathy, and in type 2 DM patients with either myocardial infarction (MI; n = 75), or with (n = 37), or without (n = 178) retinopathy. No association between the ACE gene and retinopathy in type 1 and type 2 DM patients was revealed. In the type 2 DM patients with MI, a statistically significant (P < 0.05) elevation of the D allele frequency (64%) compared to that without MI (55.3%), together with statistically nonsignificant prevalence of the DD homozygotes (41% versus 30.6%) was observed. Our data indicate that the D allele (RR 1.43) and DD genotype (RR 1.75) are risk factors for myocardial infarction in the type 2 DM patients.     

Fatty acid metabolism is enhanced in type 2 diabetic hearts

The metabolic phenotype of hearts has been investigated using rodent models of type 2 diabetes which exhibit obesity and insulin resistance: db/db and ob/ob mice, and Zucker fatty and ZDF rats. In general, cardiac fatty acid (FA) utilization is enhanced in type 2 diabetic hearts, with increased rates of FA oxidation (db/db, ob/ob and ZDF models) and increased FA esterification into cellular triacylglycerols (db/db hearts). Hearts from db/db and ob/ob mice and ZDF rat hearts all have elevated levels of myocardial triacylglycerols, consistent with enhanced FA utilization. A number of mechanisms may be responsible for enhanced FA utilization in type 2 diabetic hearts: (i) increased FA uptake into cardiac myocytes and into mitochondria; (ii) altered mitochondrial function, with up-regulation of uncoupling proteins; and (iii) stimulation of peroxisome proliferator-activated receptor-alpha. Enhanced cardiac FA utilization in rodent type 2 diabetic models is associated with reduced cardiac contractile function, perhaps as a consequence of lipotoxicity and/or reduced cardiac efficiency. Similar results have been obtained with human type 2 diabetic hearts, suggesting that pharmacological interventions that can reduce cardiac FA utilization may have beneficial effects on contractile function.     

Interleukin-2 enhances angiogenesis and preserves cardiac function following myocardial infarction

We previously demonstrated that injection of IL-2-activated natural killer (NK) cells contribute to vascular remodeling via a4b7 integrin and killer cell lectin-like receptor (KLRG) 1 and promote cardiac repair following myocardial infarction (MI). The aim of the present study is to test the hypothesis that injection of recombinant human interleukin (rhIL)-2 improves angiogenesis and preserves heart function after MI. A single IV injection of rhIL-2 two days following MI improved by 27.7% the left ventricular (LV) fractional shortening of immune competent (C57Bl6) mice, but had no effect on cardiac function of immune-deficient (NOD-SCID IL2Rγnull) mice. Immunohistochemical analysis of C57Bl6 cross sections of heart revealed that collagen deposition was reduced by 23.1% and that capillary density was enhanced in the scar area and the border zone of the infarct respectively by 22.4% and 33.6% following rhIL-2 injection. In addition, rhIL-2 enhanced 1.6-fold the in vivo endothelial cell proliferation index and 1.8-fold the number of NK cell infiltrating the infarcted heart, but had no effect on the number of cardiac CD4 and CD8 cells. In vitro, rhIL-2 activated NK cells enhanced cardiac endothelial cell proliferation by 17.2%. Here we show that a single IV injection of rhIL-2 positively impacted cardiac function by improving angiogenesis through a process involving NK cells.     

Enhanced platelet aggregability in dogs following myocardial infarction

Coronary artery ligation in beagle dogs led to an abnormal platelet response that may be similar to that observed in patients with ischemic heart disease. Platelet rich plasma (PRP) obtained from these animals was markedly more responsive to collagen induced platelet aggregation than was PRP obtained from control animals which had undergone similar surgery but without having had a coronary artery ligated. Platelet sensitivity was followed after ligation for periods up to four months. The peak response to collagen occurred three weeks following surgery, remained high for three additional weeks and then gradually returned toward normal over the ensuing ten weeks. Crossover experiments employing platelets and platelet poor plasma (PPP) from ligated and control animals demonstrated that this observation was due to a plasma factor abnormality. Further studies established that BL-3459 and certain other inhibitors of platelet aggregation were capable of normalizing this exaggerated response to collagen.     

Significance of changes in TNF-alpha and IL-10 levels in the progression of heart failure subsequent to myocardial infarction

We tested whether a decrease in the ratio of interleukin-10 (IL-10) to tumor necrosis factor-alpha (TNF-alpha) correlates with the decrease in cardiac function in heart failure. It has been suggested that TNF-alpha plays a role in the progression of heart failure, and the effect of TNF-alpha in many tissues is modulated by IL-10. Any relation of these two cytokines to heart failure has never been examined. Cardiac function was assessed by echocardiographic and hemodynamic techniques in coronary artery-ligated rats at 1, 4, 8, and 16 wk after myocardial infarction (MI). Membrane-bound and soluble fractions of TNF-alpha and IL-10 proteins, the ratio of TNF-alpha to IL-10, and TNF-alpha and IL-10 mRNA levels were analyzed. Losartan was used to modify cardiac function in rats 4 wk after MI to further validate the relation between the IL-10-to-TNF-alpha ratio and cardiac function. Cardiac function deteriorated with time in all coronary artery-ligated groups, with severe failure at 16 wk after MI. Membrane-bound and soluble TNF-alpha protein fractions were increased 1 and 4 wk after MI, whereas TNF-alpha mRNA was increased 4 and 8 wk after MI. Membrane-bound IL-10 protein and mRNA levels were decreased 4, 8, and 16 wk after MI. The decrease in the IL-10-to-TNF-alpha protein ratio in all coronary artery-ligated groups correlated with the depressed cardiac function. Losartan improved cardiac function, membrane-bound and soluble TNF-alpha and IL-10 protein levels, the ratio of IL-10 to TNF-alpha, and IL-10 mRNA. This study suggests that a decrease in IL-10 and IL-10-to-TNF-alpha ratio correlates with depressed cardiac function.     

Regulation of cardiac and renal mineralocorticoid receptor expression by captopril following myocardial infarction in rats

Myocardial infarction (MI) activates the renin-angiotensin system in the heart and increases local production of aldosterone. This hormone may increase reactive fibrosis in the myocardium favoring heart failure development. To elucidate the potential contribution of aldosterone to cardiac remodeling following MI, we evaluated the expression of mineralocorticoid receptors (MCR) in the left ventricle (LV) and kidney of rats after MI and captopril treatment. MI was induced by ligation of the coronary artery in Wistar rats, which were separated into (1) sham-operated group, (2) MI group, (3) MI-captopril treated group (cap, 50 mg kg(-1) day(-1)). One month later angiotensin converting enzyme (ACE) activity was assayed in the plasma, LV and kidney. Cardiac and renal angiotensin II (Ang II) levels were determined by ELISA and MCR mRNA expression and protein were measured by Taqman RT-PCR and Western blot, respectively. Cardiac MCR mRNA and protein levels increased nearly by 80% after MI and Cap treatment normalized cardiac MCR protein and mRNA expression. Kidney MCR expression was not affected. ACE activity increased 34% in the plasma and 83% in the LV after MI. This increase was prevented by Cap. Ang II concentration increased 225% in the LV and 193% in kidney, which was partially attenuated by Cap. Our data demonstrate upregulation of MCR in the heart following MI what may facilitate the effects of aldosterone in the ventricular remodeling process. ACE inhibitors may reduce reactive fibrosis not only by decreasing Ang II production but also by attenuating the aldosterone-signaling pathway by decreasing the expression of MCR receptors.     

Altered dipeptidyl peptidase-4 activity during the progression of hyperinsulinemic obesity and islet atrophy in spontaneously late-stage type 2 diabetic rats

Altered dipeptidyl peptidase-4 (DPP4) activity during the progression of late-stage type 2 diabetes was measured in Otsuka Long-Evans Tokushima fatty (OLETF) rats. Compared with OLETF rats subjected to 30% food restriction, food-satiated OLETF rats exhibited spontaneous hyperphagic obesity, insulin resistance, hyperglycemia, hyperinsulinemia, and increased plasma DPP4 activity during the early phase of the experiment (up to ～30 wk). Subsequently, their plasma DPP4 activity as well as their body weight, body fat, and plasma insulin concentration declined to control levels during the late phase, resulting in excessive polyuria, proteinuria, dyslipidemia, pancreatic islet atrophy, hypoinsulinemia, and diabetes, which changed from insulin-resistant diabetes to hypoinsulinemic diabetes secondary to progressive islet insufficiency, and their fasting blood glucose level remained high. Since plasma DPP4 activity demonstrated significant positive correlations with body weight and the fasting plasma insulin level but not with the fasting blood glucose level during the late stage of diabetes, body fat and fasting plasma insulin levels may be useful factors for predicting the control of plasma DPP4 activity. In contrast, pancreatic DPP4 activity was significantly increased, and the expression of pancreatic insulin was significantly reduced in late-stage diabetic OLETF rats, suggesting that a relationship exists between the activation of pancreatic DPP4 and insulin depletion in pancreatic islet atrophy. In conclusion, it is suggested that plasma DPP4 activity changes in accordance with the progression of hyperinsulinemic obesity and pancreatic islet atrophy. DPP4 activity may play an important role in insulin homeostasis.     

Neuronal nitric oxide synthase and cyclooxygenase-2 in diabetic nephropathy of type 2 diabetic OLETF rats.

Neuronal nitric oxide synthase (nNOS) and cyclooxygenase-2 (COX-2) regulate the tubuloglomerular feedback (TGF) and renin-angiotensin system (RAS) in the kidney. In type 1 diabetic rats, renal overproduction of these enzymes and their relationship to the pathogenesis of diabetic nephropathy has been demonstrated. In the present study, we histologically and immunohistochemically investigated the kidneys of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, as a model of type 2 diabetes, at 62 weeks of age (chronic phase of diabetes). The kidneys of OLETF rats showed typical diabetic nephropathy. Quantitative scores for glomerulosclerosis and interstitial fibrosis in OLETF rats were significantly higher than those of age-matched control Long-Evans Tokushima Otsuka (LETO) rats. nNOS- and COX-2-positive immunoreactions were observed in the distal tubules and collecting ducts. These reactions appeared to be more widely distributed in OLETF, and the number of nNOS-and COX-2-positive sites in the OLETF were significantly more than those in LETO rats. Expression of renin, angiotensin II, and inducible nitric oxide synthase (iNOS) were also examined immunohistochemically, and no differences between OLETF and LETO rats were observed in the distributions and the number of immunoreactive-sites. In conclusion, the overproduction of nNOS and COX-2 in the kidney of OLETF rats was confirmed, suggesting that the overproduction of nNOS and/or COX-2 does not affect the intrarenal RAS or iNOS production but does affect TGF.     

Satureja khozestanica essential oil ameliorates progression of diabetic nephropathy in uninephrectomized diabetic rats

Diabetic nephropathy is the common cause of leading to end stage of renal disease (ESRD). Satureja khozestanica essential oil (SKEO) was used as an antioxidant and antidiabetic for the inhibition of diabetic nephropathy. Forty male rats were uninephrectomized and divided in four groups randomly; group one as control, group two diabetic untreatment, groups three and four treatment with SKEO by 250 or 500 ppm in drinking water, respectively. Diabetes was induced in the second, third and fourth groups by alloxan injection subcutaneously. After eight weeks treatment, serum malondialdehyde, serum creatinine and serum urea were measured. The kidney paraffin sections were stained by periodic acid Schiff method. Glomerular volume and glomerular number were estimated by stereological rules. Glomerular sclerosis was studied semi-quantitatively. The means were compared by SPSS 13 software and Mann-Whitney test at p < 0.05. Satureja khozestanica essential oil (250 or 500 ppm) significantly inhibited the progression of glomerular hypertrophy, glomerular number loss, glomerulosclerosis, lipid peroxidation, serum urea and creatinine compared with the diabetic untreated group. The level of glomerular number, serum malondialdehyde, serum creatinine and urea in the treated groups was significantly maintained at the same level as that of the control group. In conclusion, satureja essential oil significantly can ameliorate glomerular hypertrophy, loss of glomerular number, glomerulosclerosis and attenuated serum urea and serum creatinine in diabetic rats.