Cardiac Dysfunction In Type Research Articles

Protective effects of desacyl ghrelin on diabetic cardiomyopathy.

Diabetic cardiomyopathy is a specific complication of type 2 diabetes mellitus, which causes progressive cardiac dysfunction. Desacyl ghrelin has been preliminarily demonstrated to have beneficial effects on cardiovascular system and glucose metabolism, which are both related to diabetic cardiomyopathy. The aim of this study was to investigate the protective effects of desacyl ghrelin on cardiac dysfunction, cardiac fibrosis, and cellular autophagy in a type 2 diabetic mouse model. Fourteen- to eighteen-week-old db/db diabetic and db/+ non-diabetic mice were intraperitoneally treated with desacyl ghrelin at a dosage of 100 μg/kg for ten consecutive days. Ventricular fractional shortening was examined as an indicator of cardiac function by transthoracic echocardiography. The presence of diabetic cardiomyopathy was evident by the reduction in fractional shortening shown in our examined db/db mice. Intriguingly, this reduction in fractional shortening was not observed in the hearts of db/db mice treated with desacyl ghrelin. Cardiac fibrosis (indicated by excessive collagen deposition, decreased by Adiponectin and Mmp13 expression, and up-regulated by Mmp8 expression) and impairment of autophagic signalling (indicated by decreases in Foxo3 and LC3 II-to-LC3 I ratio) were shown in the hearts of diabetic mice. All these cellular and molecular alterations were alleviated by desacyl ghrelin treatment. The key cardiac pro-survival cellular signals including AMPK, Akt, ERK1/2, and GSK3α/β were impaired in the diabetic hearts, but the administration of desacyl ghrelin attenuated these signalling impairments. These results collectively demonstrate that desacyl ghrelin protects the heart against cardiac dysfunction in type 2 diabetic mice by inhibiting excessive collagen deposition and enhancing cardiac autophagic signalling via the pro-survival cellular AMPK/ERK1/2 signalling pathways.

Hypertension Is a Conditional Factor for the Development of Cardiac Hypertrophy in Type 2 Diabetic Mice

BackgroundType 2 diabetes is frequently associated with co-morbidities, including hypertension. Here we investigated if hypertension is a critical factor in myocardial remodeling and the development of cardiac dysfunction in type 2 diabetic db/db mice.MethodsThereto, 14-wks-old male db/db mice and non-diabetic db/+ mice received vehicle or angiotensin II (AngII) for 4 wks to induce mild hypertension (n = 9–10 per group). Left ventricular (LV) function was assessed by serial echocardiography and during a dobutamine stress test. LV tissue was subjected to molecular and (immuno)histochemical analysis to assess effects on hypertrophy, fibrosis and inflammation.ResultsVehicle-treated diabetic mice neither displayed marked myocardial structural remodeling nor cardiac dysfunction. AngII-treatment did not affect body weight and fasting glucose levels, and induced a comparable increase in blood pressure in diabetic and control mice. Nonetheless, AngII-induced LV hypertrophy was significantly more pronounced in diabetic than in control mice as assessed by LV mass (increase +51% and +34%, respectively, p<0.01) and cardiomyocyte size (+53% and +31%, p<0.001). This was associated with enhanced LV mRNA expression of markers of hypertrophy and fibrosis and reduced activation of AMP-activated protein kinase (AMPK), while accumulation of Advanced Glycation End products (AGEs) and the expression levels of markers of inflammation were not altered. Moreover, AngII-treatment reduced LV fractional shortening and contractility in diabetic mice, but not in control mice.ConclusionsCollectively, the present findings indicate that type 2 diabetes in its early stage is not yet associated with adverse cardiac structural changes, but already renders the heart more susceptible to hypertension-induced hypertrophic remodeling.

A Study on Screening for Silent Cardiac Dysfunction in Type II Diabetes Mellitus

Background : India being diabetic capital, the present study was conducted to screen for cardiac dysfunctions in diabetics. Objective : To screen silent cardiac dysfunction in type II Diabetes Mellitus and correlation with duration of type II Diabetes Mellitus by non-invasive methods. Method : A prospective study of 100 established cases of type II Diabetes Mellitus without history of cardiac disorder were included in the present study. Cases were further evaluated with Chest X-ray PA View; ECG and Echocardiography. Result and interpretation : In this study the age of patients was 30-80 years (Mean age =59.08± 11.38) of which 72% were males and 28% females. 49% patients had BMI above 25. Duration of type II Diabetes was 10 years in 24% patients. Among 100 patients, 16 cases had evidence myocardial infarction. 55 cases have evidence of hypertension, 50 cases had dyslipidemia and 22 cases had cardiomegaly. Those who had duration more than 5 years showed more incidence of cardiac dysfunction. Conclusion : Many cardiac dysfunction i.e., IHD, CHF, HTN, Arrhythmias, systolic&diastolic ventricular dysfunction have been reported in type II Diabetes Mellitus. These disorders can easily be recognized by non-invasive methods without much apprehensive of invasive procedures and financial burden.

Activin A impairs insulin action in cardiomyocytes via up-regulation of miR-143

Enhanced activin A release from epicardial adipose tissue (EAT) has been linked to the development of cardiac dysfunction in type 2 diabetes (T2D). This study examined whether the inhibition of insulin action induced by epicardial adipokines in cardiomyocytes can be ascribed to alterations in miRNA expression. Expression levels of miRNAs were assessed by real-time PCR in primary adult rat cardiomyocytes (ARC) exposed to conditioned media generated from EAT biopsies (CM-EAT) from patients with and without T2D. CM-EAT-T2D altered the expression of eight miRNAs in ARC vs. CM-EAT from patients without T2D. Of these, only expression of the miR-143/145 cluster was affected by activin A in the same direction as CM-EAT-T2D. Accordingly, activin A neutralizing antibodies prevented the induction of the miR-143/145 cluster by CM-EAT-T2D. Subsequently, the impact of the miR-143/145 cluster on insulin action was investigated. Transfection of HL-1 cells with precursor-miR-143 (pre-miR-143), but not pre-miR-145, blunted the insulin-mediated phosphorylation of Akt and its substrate proline-rich Akt substrate of 40 kDa (PRAS40), and reduced insulin-stimulated glucose uptake. Also lentivirus-mediated expression of pre-miR-143 in ARC reduced insulin-induced Akt phosphorylation. These effects were ascribed to down-regulation of the miR-143 target and regulator of insulin action, the oxysterol-binding protein-related protein 8 (ORP8) in both ARC and HL-1 cells. Finally, LNA-anti-miR-143 protected against the detrimental effects of CM-EAT-T2D on insulin action in ARC. Activin A released from EAT-T2D inhibits insulin action via the induction of miR-143 in cardiomyocytes. This miRNA inhibits the Akt pathway through down-regulation of the novel regulator of insulin action, ORP8.

Diminished Autophagy Limits Cardiac Injury in Mouse Models of Type 1 Diabetes

Cardiac autophagy is inhibited in type 1 diabetes. However, it remains unknown if the reduced autophagy contributes to the pathogenesis of diabetic cardiomyopathy. We addressed this question using mouse models with gain- and loss-of-autophagy. Autophagic flux was inhibited in diabetic hearts when measured at multiple time points after diabetes induction by streptozotocin as assessed by protein levels of microtubule-associated protein light chain 3 form 2 (LC3-II) or GFP-LC3 puncta in the absence and presence of the lysosome inhibitor bafilomycin A1. Autophagy in diabetic hearts was further reduced in beclin 1- or Atg16-deficient mice but was restored partially or completely by overexpression of beclin 1 to different levels. Surprisingly, diabetes-induced cardiac damage was substantially attenuated in beclin 1- and Atg16-deficient mice as shown by improved cardiac function as well as reduced levels of oxidative stress, interstitial fibrosis, and myocyte apoptosis. In contrast, diabetic cardiac damage was dose-dependently exacerbated by beclin 1 overexpression. The cardioprotective effects of autophagy deficiency were reproduced in OVE26 diabetic mice. These effects were associated with partially restored mitophagy and increased expression and mitochondrial localization of Rab9, an essential regulator of a non-canonical alternative autophagic pathway. Together, these findings demonstrate that the diminished autophagy is an adaptive response that limits cardiac dysfunction in type 1 diabetes, presumably through up-regulation of alternative autophagy and mitophagy.

CD1d-Associated Expression of NF-κB and Cardiac Dysfunction in Diabetic and Obese Mice

In patients with obesity and diabetes mellitus, abnormal production of inflammatory factors may result in cardiovascular dysfunction. In the current study, we tested the impact of CD1d-mediated innate immune responses on the expression and activation of NFkB in the hearts of adipose diabetic (db/db) mice. Splenocytes from adult db/db and CD1d-knockout mice of both genders and their wild-type, C57BL/6 and Balb/C counterparts were examined for tumor necrosis factor (TNF)-alpha and TNF-alpha receptor type 1. The percentage of natural killer T (NKT) cells in CD3+ T cells was compared with that in nondiabetic control mice. Despite the absence of inflammatory infiltrates, the hearts of db/db mice showed alterations in TNF-alpha receptor-1 and NFkB activity, including increased expression of both the NFkB p52 and p65 subunits. In the hearts of CD1d-knockout mice, p52 expression was reduced, while p65 expression remained largely unchanged. On echocardiography, the ratio of E to A transmitral flow velocities (an indicator of diastolic function) was significantly decreased in db/db mice after they swam for 30 minutes. These results provide evidence for CD1d-mediated NFkB activation and diastolic dysfunction in the hearts of db/db mice. Therefore, CD1d-associated abnormalities of innate immune responses and TNF-alpha production in splenic tissue may contribute to NFkB activation and cardiac dysfunction in type 2 diabetes.

Impaired sonic hedgehog pathway contributes to cardiac dysfunction in type 1 diabetic mice with myocardial infarction

The incidence and mortality of myocardial infarction (MI) in diabetic patients are higher than in non-diabetic patients; however, the mechanisms by which diabetes results in cardiac dysfunction are poorly understood. The present study tested the hypothesis that an impaired sonic hedgehog (Shh) pathway contributes to cardiac dysfunction in type 1 diabetic mice with MI. Adult male C57/B6 mice and streptozotocin-induced type 1 diabetic mice were used. Myocardial proteins of Shh, Patched-1 (Ptc1), and glioma-associated oncogene-1 (Gli1) were significantly decreased in type 1 diabetic mice at 10 weeks, and this was accompanied by cardiac dysfunction. Although myocardial proteins of Shh, Ptc1, and Gli1 were significantly increased 7 days after MI compared with the sham group in control mice, these proteins were markedly decreased in streptozotocin-induced diabetic mice. Treatment with Shh pathway agonist for 21 days significantly increased Ptc1 and Gli1 proteins, enhanced capillary density, reduced the percentage myocardial infarct, and then improved cardiac function in diabetic mice with MI compared with those with no drug treatment. This treatment had no effects in control mice with MI. Conversely, treatment with Shh pathway antagonist for 21 days significantly decreased Ptc1 and Gli1 proteins, reduced capillary density, enlarged the percentage myocardial infarct, and then exacerbated cardiac dysfunction in control mice with MI compared with those with no drug treatment. These findings indicate that in type1 diabetic mice the myocardial Shh pathway is impaired and that the impaired Shh pathway contributes to cardiac dysfunction. Strategies that are aimed at augmenting the Shh pathway may offer useful means for improving diabetic cardiac dysfunction.

Pitavastatin treatment normalizes VEGF signaling and cardiac function in STZ‐induced diabetic rat hearts

Abnormal alterations in cardiac expression of vascular endothelial growth factor (VEGF) as well as its receptors and impairment in the development of coronary collaterals have recently been reported in diabetic subjects. However, the effectiveness of pharmacological intervention on these diabetic defects remains unsettled. Here, we studied the effects of statin (pitavastatin) on cardiac VEGF signaling pathways and cardiac function in Sprague‐Dawley rats 5 wk after induction of type I diabetes with streptozotocin (65 mg/kg ip) in comparison with age‐matched control rats. After streptozotocin (1 wk), some diabetic rats were treated with pitavastatin (1 mg/day) for 4 wk. VEGF, its receptors, and its angiogenic signaling molecules [phosphorylated Akt and endothelial nitric‐oxide synthase (eNOS)] were analyzed by Western blot, ELISA, real‐time PCR, and immunohistochemistry, and cardiac function was evaluated by echocardiography. Coronary capillary morphology was assessed by lectin and enzymatic double staining. We found significant decreases in cardiac expression of VEGF, its receptors, phosphorylation of Akt and eNOS, and coronary capillary density in diabetic rats compared with controls. Treatment of diabetic rats with pitavastatin reversed these alterations to control levels and ameliorated impairment of cardiac function. The present study is the first to show the potential usefulness of a statin in the treatment of cardiac dysfunction in type I diabetes at the molecular level.

Macrophage migration inhibitory factor deficiency augments cardiac dysfunction in Type 1 diabetic murine cardiomyocytes

It has become evident that macrophage migration inhibitory factor (MIF) is associated with the development of Type 1 diabetes mellitus. The aim of the present study was to determine whether MIF plays a role in cardiac contractile dysfunction in T1DM mice. Mechanical and intracellular Ca(2+) properties were measured in cardiomyocytes isolated from wild-type (WT) and MIF-knockout (MIF-KO) mice administrated or not streptozotocin (200 mg/kg, i.p.). Relative stress signaling was evaluated using western blot analysis. Peak shortening (PS) and maximal velocity of shortening/relengthening (±dL/dt) were reduced and the duration of relengthening (TR90) was prolonged in both WT and MIF-KO cardiomyocytes treated with STZ (P < 0.01 vs control), which may be associated with reduced intracellular Ca(2+) decay in both groups. However, STZ-treated WT cardiomyocytes demonstrated significantly better contractile function and intracellular Ca(2+) properties compared with STZ-treated MIF-KO cardiomyocytes (all P < 0.05). Interestingly, the physiological data clearly showed that blood glucose levels were significantly higher in STZ-treated MIF-KO mice than STZ-treated WT mice (P < 0.01). Moreover, phosphorylation of AMP-activated protein kinase (AMPK) and its direct downstream target acetyl-CoA carboxylase (ACC) was markedly lower in hearts from STZ-treated MIF-KO mice than STZ-treated WT mice (P < 0.05). There were no significant differences between untreated WT and MIF-KO control groups. There is a beneficial action of MIF in the management of cardiac dysfunction in T1DM. The cardioprotective effect of MIF may be associated with AMPK signaling.

Loss of Bradykinin Signaling Does Not Accelerate the Development of Cardiac Dysfunction in Type 1 Diabetic Akita Mice

Bradykinin signaling has been proposed to play either protective or deleterious roles in the development of cardiac dysfunction in response to various pathological stimuli. To further define the role of bradykinin signaling in the diabetic heart, we examined cardiac function in mice with genetic ablation of both bradykinin B1 and B2 receptors (B1RB2R(-/-)) in the context of the Akita model of insulin-deficient type 1 diabetes (Ins2(Akita/+)). In 5-month-old diabetic and nondiabetic, wild-type and B1RB2R(-/-) mice, in vivo cardiac contractile function was determined by left-ventricular (LV) catheterization and echocardiography. Reactive oxygen species levels were measured by 2'-7'-dichlorofluorescein diacetate fluorescence. Mitochondrial function and ATP synthesis were determined in saponin-permeabilized cardiac fibers. LV systolic pressure and the peak rate of LV pressure rise and decline were decreased with diabetes but did not deteriorate further with loss of bradykinin signaling. Wall thinning and reduced ejection fractions in Akita mouse hearts were partially attenuated by B1RB2R deficiency, although other parameters of LV function were unaffected. Loss of bradykinin signaling did not increase fibrosis in Ins2(Akita/+) diabetic mouse hearts. Mitochondrial dysfunction was not exacerbated by B1RB2R deficiency, nor was there any additional increase in tissue levels of reactive oxygen species. Thus, loss of bradykinin B2 receptor signaling does not abrogate the previously reported beneficial effect of inhibition of B1 receptor signaling. In conclusion, complete loss of bradykinin expression does not worsen cardiac function or increase myocardial fibrosis in diabetes.

NF-kappaB-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type II diabetes.

Inflammatory molecules and their transcription factor, nuclear factor kappa-B (NF-kappaB), are thought to play important roles in diabetes-induced cardiac dysfunction. Here, we investigated the effects of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, in diabetic mice. Obese db/db mice and heterozygous lean mice (n = 8) were allowed free access to drinking water (control) or water containing PDTC (100 mg/kg) for 20 weeks. Left ventricular (LV) function was measured using echocardiography at baseline and at study end. Mice were sacrificed and LV removed for gene expression, biochemical, immunofluorescence, and mitochondrial assays. LV and mitochondrial reactive oxygen species (ROS), superoxide and peroxynitrite were measured using electron spin resonance spectroscopy. Enhanced NF-kappaB activity in db/db mice was associated with increased oxidative stress as demonstrated by increased ROS, superoxide, and peroxynitrite production, and increased NF-kappaB, gp91phox, and Nox1 expression; PDTC ameliorated these effects. Mitochondrial free radical production and structural damage were higher in the db/db group than in the control, db/db PDTC, and PDTC-treated heterozygous animal groups. This study demonstrates that NF-kappaB blockade with PDTC mitigates oxidative stress and improves mitochondrial structural integrity directly, through down-regulation of increased oxygen-free radicals, thereby increasing ATP synthesis and thus restoring cardiac function in type II diabetes.

Blockage of receptor for advanced glycation end products prevents development of cardiac dysfunction in db/db type 2 diabetic mice

Activation of the receptor for advanced glycation end products (RAGE) is associated with long-term complications in diabetes mellitus. In this study, we tested whether RAGE activation in the diabetic myocardium is implicated in the development of cardiac dysfunction. Using MRI and conductance catheter techniques, we evaluated cardiac function in a type 2 diabetic mouse model (db/db), and assessed the effect of blocking RAGE with a RAGE antibody. Gene expressions were evaluated in samples of myocardial tissue. Diabetic db/db mice demonstrated an accelerated age-dependent deterioration in cardiac function associated with altered expression of genes related to cardiac structure and function. Blockage of RAGE signalling prevented the reduction in systolic function (preload recruitable stroke work: 109.8 +/- 13.8 vs. 94.5 +/- 14.9 mmHg/microL, P = 0.04) and development of increased LV diastolic chamber stiffness (0.18 +/- 0.05 vs. 0.27 +/- 0.07 mmHg, P = 0.01). The cardiac expression of collagen (col1a1) was reduced by approximately 45% and the expression of myosin was switched from the foetal isoform (MHCbeta) to the adult isoform (MHCalpha). Activation of RAGE is a significant pathogenetic mechanism for the development of cardiac dysfunction in type 2 diabetes. The underlying mechanisms involve not only the passive biophysical properties of the myocardium but also myocyte function.

Type 1 Diabetic Akita Mouse Hearts Are Insulin Sensitive but Manifest Structurally Abnormal Mitochondria That Remain Coupled Despite Increased Uncoupling Protein 3

OBJECTIVE— Fatty acid–induced mitochondrial uncoupling and oxidative stress have been proposed to reduce cardiac efficiency and contribute to cardiac dysfunction in type 2 diabetes. We hypothesized that mitochondrial uncoupling may also contribute to reduced cardiac efficiency and contractile dysfunction in the type 1 diabetic Akita mouse model (Akita).RESEARCH DESIGN AND METHODS— Cardiac function and substrate utilization were determined in isolated working hearts and in vivo function by echocardiography. Mitochondrial function and coupling were determined in saponin-permeabilized fibers, and proton leak kinetics was determined in isolated mitochondria. Hydrogen peroxide production and aconitase activity were measured in isolated mitochondria, and total reactive oxygen species (ROS) were measured in heart homogenates.RESULTS— Resting cardiac function was normal in Akita mice, and myocardial insulin sensitivity was preserved. Although Akita hearts oxidized more fatty acids, myocardial O2 consumption was not increased, and cardiac efficiency was not reduced. ADP-stimulated mitochondrial oxygen consumption and ATP synthesis were decreased, and mitochondria showed grossly abnormal morphology in Akita. There was no evidence of oxidative stress, and despite a twofold increase in uncoupling protein 3 (UCP3) content, ATP-to-O ratios and proton leak kinetics were unchanged, even after perfusion of Akita hearts with 1 mmol/l palmitate.CONCLUSIONS— Insulin-deficient Akita hearts do not exhibit fatty acid–induced mitochondrial uncoupling, indicating important differences in the basis for mitochondrial dysfunction between insulin-responsive type 1 versus insulin-resistant type 2 diabetic hearts. Increased UCP3 levels do not automatically increase mitochondrial uncoupling in the heart, which supports the hypothesis that fatty acid–induced mitochondrial uncoupling as exists in type 2 diabetic hearts requires a concomitant increase in ROS generation.

Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts

Abnormal alterations in cardiac expression of vascular endothelial growth factor (VEGF) as well as its receptors and impairment in the development of coronary collaterals have recently been reported in diabetic subjects. However, the presence of pharmacological intervention on these defects in diabetes remains unsettled. Here, we studied the effect of endothelin (ET) receptor blockade on cardiac VEGF signaling pathways and cardiac function in Sprague-Dawley rats 5 wk after induction of type I diabetes with streptozotocin (65 mg/kg ip) in comparison with age-matched control rats. After streptozotocin (1 wk), some diabetic rats were treated with the ET receptor antagonist SB-209670 (1 mg/day) for 4 wk. VEGF, its receptors, and its angiogenic signaling molecules [phosphorylated Akt and endothelial nitric-oxide synthase (eNOS)] were analyzed by Western blot, ELISA, real-time PCR, and immunohistochemistry, and cardiac function was evaluated by echocardiography. Coronary capillary morphology was assessed by lectin and enzymatic double staining. We found significant decreases in cardiac expression of VEGF, its receptors, phosphorylation of Akt and eNOS, and coronary capillary density in diabetic rats compared with controls. Treatment of diabetic rats with SB-209670 reversed these alterations to the control levels and ameliorated impairment of cardiac function. From a molecular point of view, the present study is the first to indicate the potential usefulness of an ET receptor antagonist in the treatment of cardiac dysfunction in type I diabetes.