Abnormal Myocardial Architecture Research Articles

Pathological involvement of apoptotic and inflammatory molecules in cardiovascular remodeling in rats on high fructose diet-induced metabolic syndrome.

Fructose consumption has been linked to manifestation of metabolic syndrome (MS); an emerging epidemic. The current study attempts to demonstrate fructose overconsumption-mediated cardiovascular disease (CVD) remodeling in Wistar rats. Rats were randomly segregated into control (CON) and high fructose diet (FFR) groups and received customized diets for 20weeks. Levels of diabetic, lipid, antioxidant, markers, mRNA levels of inflammatory, apoptotic markers, and histopathological changes were assessed in excised hearts of both groups. Significant increase in uric acid, pro-oxidants diabetic, lipid, inflammatory markers, cytosolic cytochrome C, nuclear NF-кB-p65, and decrease in antioxidants was observed in FFR group. Abnormal myocardial architecture was observed in the FFR group along with elevated mRNA levels of inflammatory, apoptotic markers, and MMP-9, -2. The outcomes of the study are suggestive of role of aforementioned molecules in high fructose intake-mediated pathological deterioration of heart and development of MS-associated CVD progression. PRACTICAL APPLICATIONS: Excessive fructose consumption in the form of high fructose corn syrup, sugary drinks, and commonly available fast foods has been shown to be linked with many diseases such as liver malfunction, metabolic syndrome diabetes, and cardiovascular diseases. However, delineated pathways and clear mechanisms and their role in cardiovascular remodeling due to excessive fructose consumption are yet to be established. The present study establishes the deleterious effects of foods with high sugar content on progression toward metabolic syndrome and cardiovascular remodeling. It further investigates the role of different pathways involved in the development of high fructose-induced diet-induced metabolic syndrome, and thereby leading to harmful effects on the hearts of rats consuming high fructose diet leading to cardiovascular in Wistar rats. The study suggests the role of immunomodulation and oxidative stress in the remodeling of cardiac muscles and in turn progression toward metabolic syndrome and cardiovascular remodeling. The study, therefore, throws light on the deleterious effects of consumption of foods and easily available fast foods on progression toward numerous non-communicable diseases.

Coxsackievirus B3 Infection Early in Pregnancy Induces Congenital Heart Defects Through Suppression of Fetal Cardiomyocyte Proliferation.

BackgroundCoxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation.Methods and ResultsWe infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose‐response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double‐outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3‐exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor‐β1, and extracellular matrix proteins were the most highly enriched in CVB3‐infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls.ConclusionsWe conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes.

Cardioprotective activity of Piper betle juice in isoproterenol induced hypertrophic rat models

Impaired electrolytes (preferably Na+, K+, Cl-, HCO3-) is one of the key fundamental complications associated with cardiac hypertrophy (enlarged heart) mediated heart failure. Piper betle (P. betle - family Piperaceae) due to its potent antioxidant activity is used in various pharmacological applications. The present study evaluates the cardioprotective (anti-hypertrophic) potential of aqueous (juice) extract of P. betle in restoring electrolyte homeostasis, thereby its ability to curb the fundamental progression of hypertrophy. Isoproterenol (ISO - 10 mg/kg b.w., i.p., 7 days) induced cardiac hypertrophic rats were developed that were simultaneously treated with the standard drug losartan (50mg/kg b.w., orally., 7days) and aqueous juice extract of P. betle (30mg/kg b.w., orally., 7 days). The biochemical estimation of glucose, protein, cholesterol, cardiac marker enzymes like SGOT, SGPT, LDH, enzymatic antioxidants namely SOD, catalase, GPx and electrolytes (Na+, K+, Cl- and bicarbonate) in serum were statistically performed along with the histopathological analysis of left ventricles (H&E stain). The present study showed increased levels of glucose, protein, cholesterol, cardiac marker enzymes, reduced enzymatic antioxidants with reduced electrolytes during cardiac hypertrophy (ISO) that were reflected in a histopathological analysis by thickened abnormal myocardial architecture which was reversed similar to normal in plant juice administered rats. Hence, this study demonstrated the beneficial effect of P. betle (aqueous juice) on electrolytes (Na+, K+, Cl-, HCO3-), thereby imposing an interventional effect against cardiac hypertrophy.

Abstract 16914: Structural and Functional Investigation of Myocardial Fiber Architecture in Genetic Mouse Models of Heterodoxy and Situs Inverses Totalis

Introduction: Heterotaxy (HTX) patients with congenital heart disease have higher risk of post-surgical complications and increased morbidity and mortality. Given HTX involves disruption of left-right patterning, this suggests laterality disturbance may drive the poor outcome in CHD patients with HTX. To investigate this, we used mouse models with laterality defects. Although HTX mutant mice invariably die prenatally/neonatlly from complex CHD, many mutations causing HTX also giive rise to mice that are adult viable with situs inversus totalis (SIT), or situs solitus (SS) without CHD. Hence, our goal is to delineate myocardial fiber architecture in the SIT and SS mutant mice to gain insights into possible functional deficits associated with HTX. Hypothesis: Disturbance in specification of laterality results in abnormal myocardial fiber architecture that can cause cardiac dysfunction and make the heart more vulnerable to stress. Methods: Diffusion tensor imaging (DTI) was used to delineate the myocardial fiber organization in SIT and SS mutant mice, and wild-type (WT) control mice. Cardiac MRI and echocardiography were used to evaluate cardiac function with or without dobutamine stress. Results: Echocardiography showed no significant differences in global systolic function in the SIT and SS mutant hearts, but they displayed compromised strain rates under dobutamine stress. SIT and SS hearts also exhibited reduced rotation and torsion, suggesting altered myocardial fiber organization. Myocardial tractography by DTI (Fig.A-D) showed less coherent myocardial fiber organization (Fig. G-I) and more diverse helix angles (Fig. K&M) in SIT mutant hearts. Overall, our data showed the mutant SS and SIT hearts have disrupted myocardial fiber architecture resulting in abnormal torsion, rotation, and strain when stressed. Conclusions: These findings suggest abnormal myocardial architecture may contribute to the poor clinical outcome in HTX patients with CHD.

GABA tea attenuates cardiac apoptosis in spontaneously hypertensive rats (SHR) by enhancing PI3K/Akt-mediated survival pathway and suppressing Bax/Bak dependent apoptotic pathway.

Cardiomyocyte apoptosis is the major risk factor for the development of heart failure (HF). The purpose of this study was to evaluate the effects of Gamma-aminobutyric acid (GABA) tea on hypertension-induced cardiac apoptotic pathways in spontaneously hypertensive rats (SHR). In order to reveal the mechanisms, 36 male SHR at eight weeks of age, 200 g were divided into six groups. One group was fed water as a control group. Other rats were administered one of the following treatments: GABA tea at dose 150 and 300 mg/kg/day as low GABA tea (LGT) and high GABA tea (HGT) groups, respectively, pure GABA at dose 150 and 300 mg/kg/day as LG and HG groups, respectively, green tea (GT) as control of LGT and HGT groups. After 12 weeks, cardiac tissues were analyzed by histological analysis, western blotting, and TUNEL assays. GABA tea, GT, and pure GABA decreased hypertension-induced cardiac abnormalities, including abnormal myocardial architecture. In addition, GABA tea, GT, and pure GABA dramatically increased anti-apoptotic protein, Bcl2. Furthermore, GABA tea, GT, and pure GABA also decreased activated-caspase 9 and activated-caspase 3. Additionally, the survival associated protein IGF-I and PI3K/Akt were enhanced in cardiac tissues upon treatment. Our results showed an optimistic anti-apoptotic and pro-survival effects of GABA tea treatment against hypertensive rat hearts.

Antiapoptotic effect of exercise training on ovariectomized rat hearts.

The purpose of this study was to evaluate the effects of exercise training on cardiac Fas receptor-dependent and mitochondria-dependent apoptotic pathways in ovariectomized rats. Histopathological analysis, TUNEL assay, and Western blotting were performed on the excised hearts from three groups of Sprague-Dawley rats, which were divided into a sham-operated group, a bilaterally ovariectomized group (OVX), and a bilaterally ovariectomized group that underwent treadmill running exercise for 60 min/day, 5 sessions/wk, for 10 wk (OVX-EX). The abnormal myocardial architecture, cardiac trichome-stained fibrosis and cardiac TUNEL-positive apoptotic cells in ovariectomized rats improved after exercise training. The protein levels of tumor necrosis factor-α, tumor necrosis factor receptor 1, Fas ligand, Fas receptors, Fas-associated death domain, activated caspase-8 and activated caspase-3 (Fas receptor-dependent apoptotic pathways), as well as t-Bid, Bad, Bak, Bax, cytosolic cytochrome c, activated caspase-9, and activated caspase-3 (mitochondria-dependent apoptotic pathways) were decreased in the OVX-EX group compared with the OVX group. Exercise training suppressed ovariectomy-induced cardiac Fas receptor-dependent and mitochondria-dependent apoptotic pathways in ovariectomized rat models. These findings might indicate a new therapeutic effect for exercise training to prevent cardiac apoptosis in menopausal or bilaterally oophorectomized women.

Multi-Strain Probiotics Inhibit Cardiac Myopathies and Autophagy to Prevent Heart Injury in High-Fat Diet-Fed Rats

High-fat diets induce obesity, leading to cardiomyocyte fibrosis and autophagy imbalance. In addition, no previous studies have indicated that probiotics have potential health effects associated with cardiac fibrosis and autophagy in obese rats.This study investigates the effects of probiotics on high-fat (HF) diet-induced obesity and cardiac fibrosis and autophagy in rat hearts. Eight-week-old male Wistar rats were separated randomly into five equally sized experimental groups: Normal diet (control) and high-fat (HF) diet groups and groups fed a high-fat diet supplemented with low (HL), medium (HM) or high (HH) doses of multi-strain probiotic powders. These experiments were designed for an 8-week trial period. The myocardial architecture of the left ventricle was evaluated using Masson's trichrome staining and immunohistochemistry staining. Key probiotics-related pathway molecules were analyzed using western blotting. Abnormal myocardial architecture and enlarged interstitial spaces were observed in HF hearts. These interstitial spaces were significantly decreased in groups provided with multi-strain probiotics compared with HF hearts. Western blot analysis demonstrated that key components of the TGF/MMP2/MMP9 fibrosis pathways and ERK5/uPA/ANP cardiac hypertrophy pathways were significantly suppressed in probiotic groups compared to the HF group. Autophagy balance is very important in cardiomyocytes. In this study, we observed that the beclin-1/LC3B/Atg7 autophagy pathway in HF was increased after probiotic supplementation was significantly decreased. Together, these results suggest that oral administration of probiotics may attenuate cardiomyocyte fibrosis and cardiac hypertrophy and the autophagy-signaling pathway in obese rats.

Alterations in left ventricular function during intermittent hypoxia: Possible involvement of O-GlcNAc protein and MAPK signaling.

Obstructive sleep apnea, characterized by recurrent episodes of hypoxia [intermittent hypoxia (IH)], has been identified as a risk factor for cardiovascular diseases. The O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) of proteins has important regulatory implications on the pathophysiology of cardiovascular disorders. In this study, we examined the role of O-GlcNAcylation in cardiac architecture and left ventricular function following IH. Rats were randomly assigned to a normoxia and IH group (2 min 21% O2; 2 min 6–8% O2). Left ventricular function, myocardial morphology and the levels of signaling molecules were then measured. IH induced a significant increase in blood pressure, associated with a gradually abnormal myocardial architecture. The rats exposed to 2 or 3 weeks of IH presented with augmented left ventricular systolic and diastolic function, which declined at week 4. Consistently, the O-GlcNAc protein and O-GlcNAcase (OGA) levels in the left ventricular tissues steadily increased following IH, reaching peak levels at week 3. The O-GlcNAc transferase (OGT), extracellular signal-regulated kinase 1/2 (ERK1/2) and the p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation levels were affected in an opposite manner. The phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) remained unaltered. In parallel, compared with exposure to normoxia, 4 weeks of IH augmented the O-GlcNAc protein, OGT, phosphorylated ERK1/2 and p38 MAPK levels, accompanied by a decrease in OGA levels and an increase in the levels of myocardial nuclear factor-κB (NF-κB), inflammatory cytokines, caspase-3 and cardiomyocyte apoptosis. Taken together, our suggest a possible involvement of O-GlcNAc protein and MAPK signaling in the alterations of left ventricular function and cardiac injury following IH.

Cardiac Fas-Dependent and Mitochondria-Dependent Apoptotic Pathways in a Transgenic Mouse Model of Huntington's Disease.

Huntington's disease is an autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the huntingtin gene. Heart disease is the second leading cause of death in patients with Huntington's disease. This study was to evaluate whether cardiac Fas-dependent and mitochondria-dependent apoptotic pathways are activated in transgenic mice with Huntington's disease. Sixteen Huntington's disease transgenic mice (HD) and sixteen wild-type (WT) littermates were studied at 10.5weeks of age. The cardiac characteristics, myocardial architecture, and two major apoptotic pathways in the excised left ventricle from mice were measured by histopathological analysis, Western blotting, and TUNEL assays. The whole heart weight and the left ventricular weight decreased significantly in the HD group, as compared to the WT group. Abnormal myocardial architecture, enlarged interstitial spaces, and more cardiac TUNEL-positive cells were observed in the HD group. The key components of Fas-dependent apoptosis (TNF-alpha, TNFR1, Fas ligand, Fas death receptors, FADD, activated caspase-8, and activated caspase-3) and the key components of mitochondria-dependent apoptosis (Bax, Bax-to-Bcl-2 ratio, cytosolic cytochrome c, activated caspase-9, and activated caspase-3) increased significantly in the hearts of the HD group. Cardiac Fas-dependent and mitochondria-dependent apoptotic pathways were activated in transgenic mice with Huntington's disease, which might provide one of possible mechanisms to explain why patients with Huntington's disease will develop heart failure.

Effects of lactic acid bacteria on cardiac apoptosis are mediated by activation of the phosphatidylinositol-3 kinase/AKT survival-signalling pathway in rats fed a high-fat diet.

Through a high-fat diet, obesity leads to cardiomyocyte dysfunction and apoptosis. In addition, there is no evidence that probiotics have potential health effects associated with cardiac apoptosis in obese rats. The present study aimed to explore the effects of probiotics on obesity and cardiac apoptosis in rats fed a high-fat diet (HF). Eight‑week‑old male Wistar rats were separated randomly into five equally sized experimental groups: Normal diet (NC) and high-fat diet (HFC) groups, and high-fat diet supplemented with low (HFL), medium (HFM) or high (HFH) doses of multi‑strain probiotics groups. The rats were subsequently studied for 8 weeks. Food intake and body weights were recorded following sacrifice, and food utilization rates, body fat and serum cholesterol levels were analysed. The myocardial architecture of the left ventricle was evaluated by hematoxylin‑eosin staining, and key apoptotic‑related pathway molecules were analysed by western blotting. Rat weights and triglyceride levels were decreased with oral administration of high doses of probiotics (HFH) compared to the HFC group. Abnormal myocardial architecture and enlarged interstitial spaces were observed in HFC hearts, but were significantly decreased in groups that were provided multi‑strain probiotics compared with NC hearts. Western blot analysis demonstrated that key components of the Fas receptor‑ and mitochondrial‑dependent apoptotic pathways were significantly suppressed in multi‑strain probiotic treated groups compared to the HF group. Additionally, cardiac insulin, such as the insulin‑like growth factor I receptor (IGFIR)‑dependent survival signalling components, were highly induced in left ventricles from rats administered probiotics. Together, these findings strongly suggest that oral administration of probiotics may attenuate cardiomyocyte apoptosis by activation of the phosphatidylinositol‑3 kinase/AKT survival‑signalling pathway in obese rats.

Prolactin protects cardiomyocytes against intermittent hypoxia-induced cell damage by the modulation of signaling pathways related to cardiac hypertrophy and proliferation

ObjectivesProlactin (PRL) is a multifunctional hormone that influences multiple physiological processes. It has been shown to have a protective effect on the cardiovascular system; however, the mechanisms of this effect are poorly understood. The purpose of the study was to elucidate the role of PRL in intermittent hypoxia (IH)-induced apoptosis in the cardiovascular system. Method and resultsWe established a hyperprolactinemic rat model by implanting two anterior pituitary (AP) glands into the renal capsule of male Sprague–Dawley rats. The rats were kept under normoxic conditions for 4weeks after implantation in order to reach the expression plateau of PRL in the plasma, and then treated with IH for 7 or 14days. Their hearts were then removed for histological and protein expression analyses. Cerebral cortex (CX)-grafted control rats challenged with IH displayed unique phenotypes such as a thicker heart wall, an abnormal myocardial architecture and an increased interstitial space of the left ventricle. They exhibited reduced expressions of p-JAK2, p-STAT5, cell cycle-dependent proteins (cyclin D1, cyclin E and cyclin A), IGF-IRα, PI3Kα, p-AKT and p-ERK1/2 in cardiomyocytes at 7days. ConclusionsOur comprehensive analysis suggested that high plasma PRL can protect rat cardiomyocytes against IH through (1) the p-JAK2 and p-STAT5 pathways for transient cell proliferation, (2) the PI3Kα/AKT and MAPK survival pathways through IGF-I, and (3) the downregulation of IGF-II and ERK5, which inhibit cell hypertrophy.

Chronic Methamphetamine Exposure Induces Cardiac Fas-Dependent and Mitochondria-Dependent Apoptosis

Very limited information regarding the influence of chronic methamphetamine exposure on cardiac apoptosis is available. In this study, we evaluate whether chronic methamphetamine exposure will increase cardiac Fas-dependent (type I) and mitochondria-dependent (type II) apoptotic pathways. Thirty-two male Wistar rats at 3-4 months of age were randomly divided into a vehicle-treated group [phosphate-buffered saline (PBS) 0.5 ml SQ per day] and a methamphetamine-treated group (MA 10 mg/kg SQ per day) for 3 months. We report that after 3 months of exposure, abnormal myocardial architecture, more minor cardiac fibrosis and cardiac TUNEL-positive apoptotic cells were observed at greater frequency in the MA group than in the PBS group. Protein levels of TNF-α, Fas ligand, Fas receptor, Fas-associated death domain, activated caspase-8, and activated caspase-3 (Fas-dependent apoptosis) extracted from excised hearts were significantly increased in the MA group, compared to the PBS group. Protein levels of cardiac Bak, t-Bid, Bak to Bcl-xL ratio, activated caspase-9, and activated caspase-3 (mitochondria-dependent apoptosis) were significantly increased in the MA group, compared with the PBS group. The results from this study reveal that chronic methamphetamine exposure will activate cardiac Fas-dependent and mitochondria-dependent apoptotic pathways, which may indicate a possible mechanism for developing cardiac abnormalities in humans with chronic methamphetamine abuse.

Activated apoptotic and anti‐survival effects on rat hearts with fructose induced metabolic syndrome

Consumption of fructose has been linked to the development of metabolic syndrome, whereas the cardiomyopathic changes and cardiac apoptosis of dietary high-fructose intake have not yet been clarified. The purpose of this study was to evaluate the effects of high-fructose on cardiac apoptotic and survival pathways. Thirty-two Wistar rats were randomly divided into a control group (CON), which received a standard chow diet, and a fructose-induced metabolic syndrome group (FIMS), which received a 50% fructose-content diet for 13 weeks. Histopathological analysis, TUNEL assays and Western blotting were performed on the excised hearts from both groups. The blood pressure, glucose, insulin, triglyceride and cholesterol levels were significantly increased in the FIMS group, compared with the CON group. The abnormal myocardial architecture, enlarged interstitial space and increased cardiac TUNEL-positive apoptotic cells were observed in the FIMS group. The TNF-α, TNF receptor 1, Fas ligand, Fas receptor, FADD, and activated caspase-3 and 8 protein levels (Fas pathway) and the Bax, Bak, Bax/Bcl-2, Bak/Bcl-xL, cytosolic cytochrome c, and activated caspase-3 and nine protein levels (mitochondria pathway) were increased in the FIMS group compared with those in the CON group. The IGFI, IGFI-R, p-PI3K, p-Akt, Bcl-2 and Bcl-xL protein levels (survival pathway) were all significantly decreased in the FIMS group compared with those in the CON group. High-fructose intake elevated blood pressure and glucose levels; moreover, high-fructose diet activated cardiac Fas-dependent and mitochondria-dependent apoptotic pathways and suppressed the survival pathway, which might provide one possible mechanism for developing heart failure in patients with metabolic syndrome.

Inhibition of cardiac hypertrophy by probiotic-fermented purple sweet potato yogurt in spontaneously hypertensive rat hearts

Cardiovascular hypertrophy is a common feature of hypertension and an important risk factor for heart damage. The regression of cardiovascular hypertrophy is currently considered an important therapeutic target in reducing the omplications of hypertension. The aim of this study was to investigate the inhibition of cardiac hypertrophy by probiotic-fermented purple sweet potato yogurt (PSPY) with high γ-aminobutyric acid (GABA) content in spontaneously hypertensive rat (SHR) hearts. Six-week-old male SHRs were separated randomly and equally into 4 experimental groups: sterile water, captopril and 2 PSPY groups with different doses (10 and 100%) for 8 weeks. The changes in myocardial architecture and key molecules of the hypertrophy-related pathway in the excised left ventricle from these rats were determined by histopathological analysis, hematoxylin and eosin staining and western blot analysis. Abnormal myocardial architecture and enlarged interstitial spaces observed in the SHRs were significantly decreased in the captopril and PSPY groups compared with the sterile water group. Moreover, the increases in atrial natriuretic peptide, B-type natriuretic peptide, phosphorilated protein kinase Cα and calmodulin-dependent protein kinase II levels in the left ventricle were accompanied by hypertension and increases in phosphorylated extracellular signal-regulated kinase 5 activities with enhanced cardiac hypertrophy. However, the protein levels of the hypertrophic-related pathways were completely reversed by the administration of PSPY. PSPY may repress the activation of ANP and BNP which subsequently inhibit the dephosphorylation of the nuclear factor of activated T-cells, cytoplasmic 3 and ultimately prevent the progression of cardiac hypertrophy.

Exercise training enhances cardiac IGFI-R/PI3K/Akt and Bcl-2 family associated pro-survival pathways in streptozotocin-induced diabetic rats

BackgroundIncreased myocyte apoptosis in diabetic hearts has been previously reported. The purpose of this study was to evaluate the effects of exercise training on cardiac survival pathways in streptozotocin (STZ)-induced diabetic rats. MethodsForty-eight male Wistar rats were randomly divided into control group (Control), STZ-induced (65mg/kg, i.p.) diabetes (DM), and DM rats with moderate aerobic exercise training (DM-EX) on a treadmill 60min/day, 5days/week, for 10weeks. Histopathological analysis, positive TUNEL assays and Western blotting were performed on the excised cardiac left ventricles from all three groups. ResultsThe components of cardiac survival pathway (insulin-like growth factor I (IGFI), IGFI-receptor (IGFI-R), phosphatidylinositol 3′-kinase (PI3K), and Akt) and the pro-survival Bcl-2 family proteins (Bcl-2, Bcl-xL, and p-BAD) were all significantly decreased in the DM group compared with the Control group whereas they were increased in the DM-EX group. In addition, the abnormal myocardial architecture, enlarged interstitial space and increased cardiac TUNEL-positive apoptotic cells were observed in the DM group, but they were reduced in the DM-EX group. The apoptotic key component, caspase-3, was significantly increased in the DM group relative to the Control group whereas it was decreased in the DM-EX group. ConclusionsExercise training enhances cardiac IGFI-R/PI3K/Akt and Bcl-2 family associated pro-survival pathways, which provides one of the new beneficial effects for exercise training in diabetes.

The Coexistence of Aging and Obesity Additively Increase Cardiac Apoptosis

PURPOSE: Cardiac apoptosis were found in obesity, but the cardiac molecular mechanism in the aging obesity were not available. The purpose of this study was to evaluate whether the aging and obesity will additively influence the apoptotic pathways. METHODS: Eleven young lean (YL), 10 young obese (YO), 11 old lean (OL), and 11 old obese (OO) Zucker rats were investigated at 4 and 14 months old. The cardiac characteristics, apoptotic levels and their related pathways in the excised left ventricle form rats were measured by heart weight index, histological analysis, positive TUNEL assays, H&E stain, and Western blotting. RESULTS: Compared with YL group, the whole heart weight, the abnormal myocardial architecture, and TUNEL-positive apoptotic cells were significantly higher in YO, OL or OO groups. The activity of cardiac Fas receptor-dependent apoptotic pathway (Fas L, Fas, FADD, caspase-8, caspase-3), mitochondrial -dependent apoptotic pathway (Bad, cytosolic cytochrome c, caspase-9,, caspase-3) and transition from Fas- to mitochondrial-dependent apoptotic pathway (tBid) were significantly higher in YO, OL or OO groups than those in YL group. These pathways were higher in OO group than either YO or OL groups. CONCLUSIONS: The coexistence of aging and obesity additively increase cardiac Fas receptor and mitochondrial -dependent apoptosis. These findings may provide a possible apoptotic mechanism for developing heart failure in aging obesity.

Enhanced cardiac Fas and mitochondrial dependent apoptosis in high fructose‐induced Metabolic Syndrome

No information has been published regarding cardiac apoptosis in high fructose‐induced Metabolic Syndrome. The purpose of this study was to evaluate whether cardiac Fas‐dependent and mitochondria‐dependent apoptotic pathways are activated in high fructose‐induced Metabolic Syndrome. Ten high fructose induced Metabolic Syndrome (FIMS) and 10 normal diet control were studied at 3–4 months of age. The cardiac characteristics, myocardial architecture, and two major apoptotic pathways in the excised left ventricle from rats were measured by histopathological analysis, western blotting and TUNEL assays. Abnormal myocardial architecture, enlarged interstitial spaces, and more cardiac TUNEL‐positive apoptotic cells were observed in FIMS. The key components of Fas‐dependent apoptosis (Fas ligand, Fas death receptors, FADD, activated caspase 8, and activated caspase 3) and key components of mitochondria‐dependent apoptosis (Bax, Bax‐to‐Bcl2 ratio, cytosolic cytochrome c, activated caspase 9, and activated caspase 3) were significantly increased in FIMS hearts. Conclusions. Cardiac Fas‐dependent and mitochondria‐dependent apoptotic pathways are activated in high fructose‐induced Metabolic Syndrome, which might provide one of possible mechanism for developing heart diseases in patients with diet‐induced Metabolic Syndrome.

072 Chemical denervation of sympathetic nervous system induces abnormal myocardial architecture

The aim of the present work was to investigate changes in heart architecture after chemical sympathetic denervation by 6OH-Dopamine (6OH-DA) in mice. Two months old mice (n=18) received 3 6OH-DA injections (200 mg/kg, ip) or saline (n = 6) at 3 days of interval. 15 and 30 days after first injection, heart rate spectral variability (HRV, FFT) was analyzed in low frequency (LF: 0.15-1.5 Hz) and high frequency (HF: 1.5-5 Hz) ranges and LH/HF ratio was calculated. After sacrifice, blood was withdrawn for catecholamine determination (HPLC). Hearts were fixed (formaldehyde 10%) for histology or frozen for western blot analysis (tyrosine hydroxylase, TH). Indicate that compared to controls (1410±145 pg/ml) plasma norepinephrine levels were significantly lower at D15 (766±186 pg/ml) and D30 (675±288 pg/ml) after 6OH-DA without change in epinephrine. TH expression was absent at D15 and significantly lower than in controls at D30. When compared to controls (48.5±6.2%), LF HRV was significantly reduced at D15 (31.6±5.4%) but not at D30 (58.2±16.2%) without change in HF. LF/HF ratio was lower in 6OH-DA treated mice at D15 (0.5±0.1 vs 1.3±0.2 in controls) but not at D30 (1.6±0.3). At D15, 6-OH-DA hearts exhibited mild structural abnormalities with wavy cardiomyocyte appearance in septum. At D30, histological abnormalities were diffuse with myocytes intersecting at various angles with bundles wavy appearance. Variability in cell size with anisocaryosis, attenuated myocytes with perinuclear halo and shaped nuclei were observed. No inflammation, interstitial fibrosis or necrosis was noticed. This study suggests that heart denervation induces myocardial tissue disorganization. Relationship between these changes and sympathetic nerve destruction and/or catecholamine depletion remains to be elucidated. Apart from physiological significance, these results also bring new structural basis to explain increased risk of cardiac disease during autonomic failure.

P3.10 Chemical denervation of sympathetic nervous system induces abnormal myocardial architecture

P3.10 Chemical denervation of sympathetic nervous system induces abnormal myocardial architecture

I005 Chemical denervation of sympathetic nervous system induces abnormal myocardial architecture

The role of autonomic nervous system (ANS) on heart function modulation is well-known. By contrast, ANS role on myocardial tissue architecture has scarcely been investigated. The aim of the present work was to investigate changes in heart tissue architecture after chemical sympathetic denervation by 6OH-Dopamine (6OH-DA) in mice. Two months old mice (n=18) received 3 injections of 6OHDA (200 mg/kg, ip) or saline (n = 6) at 3 days of interval. At 15 and 30 days after first injection, ECG was recorded (PowerLab, DSI) under anaesthesia and heart rate spectral variability (HRV) was performed (FFT) in low frequency (LF: 0.15-1.5 Hz) and high frequency (HF: 1.5-5 Hz) ranges; LH/HF ratio was also calculated. After sacrifice, blood was withdrawn for plasma catecholamine determination (HPLC). Heart tissue was fixed (formaldehyde 10 %) for histology or frozen for western blot analysis (tyrosine hydroxylase, TH). When compared to controls (1410±145 pg/ml) plasma norepinephrine levels were significantly lower at D15 (766±186 pg/ml) and D30 (675±288 pg/ml) after 6OH-DA without significant change in epinephrine levels. TH expression was absent at D15 and present but significantly lower than in controls at D30. When compared to controls (48.5±6.2 %), LF HRV was significantly reduced at D15 (31.6±5.4 %) but not at D30 (58.2±16.2 %) without any change in HF. LF/HF ratio was lower in 6OH-DA treated mice at D15 (0.49±0.13 vs 1.29±0.17 in controls) but was normal at D30 (1.63±0.31). At D15, hearts from 6-OH-DA treated mice exhibited mild structural abnormalities with wavy cardiomyocyte appearance in septum. At D30, histological abnormalities concerned whole myocardium with myocytes intersecting at various angles with bundles wavy appearance. Variability in cell size with anisocaryosis, attenuated myocytes with perinuclear halo and shaped nuclei were observed. No inflammation, interstitial fibrosis or necrosis were noticed. This study suggests that heart denervation induces myocardial tissue disorganization. Relationship between these pathological changes and sympathetic nerve destruction and/ or catecholamine depletion remains to be elucidated. Apart from physiological significance, these results also bring new structural basis to explain increased risk of cardiac disease during human autonomic failure.