Decreased Heart Weight Research Articles

Targeted disruption of the heat shock protein 20–phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy

Phosphorylated heat shock protein 20 (HSP20) is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20–phosphodiesterase 4D (PDE4D) complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20–PDE4D interaction leads to attenuation of pathological cardiac remodelling.

Protective actions of melatonin against heart damage during chronic Chagas disease

Chronic cardiomyopathy is the most important clinical form of Chagas disease, and it is characterised by myocarditis that is associated with fibrosis and organ dysfunction. Alternative treatment options are important tools to modulate host immune responses. The main goal of this work was to evaluate the anti-inflammatory actions of melatonin during the chronic phase of Chagas disease. TNF-α, IL-10 and nitrite concentrations were evaluated as predictive factors of immune modulation. Creatine phosphokinase-MB (CK-MB), cardiac inflammatory foci and heart weight were assessed to evaluate the efficacy of the melatonin treatment. Male Wistar rats were infected with 1×105 blood trypomastigotes of the Y strain of Trypanosoma cruzi and kept untreated for 60 days to mimic chronic infection. After this period, the rats were orally treated with melatonin 50mg/kg/day, and the experiments were performed 90, 120, and 180 days post-infection. Melatonin treatment significantly increased the concentration of IL-10 and reduced the concentrations of NO and TNF-α produced by cardiomyocytes. Furthermore, it led to decreased heart weight, serum CK-MB levels and inflammatory foci when compared to the untreated and infected control groups. We conclude that melatonin therapy is effective at protecting animals against the harmful cardiac inflammatory response that is characteristic of chronic T. cruzi infection.

A 26-week repeated-dose toxicity study of allisartan isoproxil in Sprague-Dawley rats

Allisartan isoproxil (ALS-3) is a selective, nonpeptide blocker of the angiotensin II type 1 receptor. It is a new antihypertensive drug under development with a novel chemical structure. The aim of this study was to evaluate the potential toxicity of ALS-3 in Sprague-Dawley rats. Animals were orally administered either vehicle or ALS-3 at doses of 20, 80 and 320 mg/kg once-daily for 26 weeks, followed by a 6-week recovery period. Toxicity was assessed by mortality, clinical signs, body weight, food consumption, hematology, coagulation, serum chemistry, gross necropsy, organ weights and microscopic examination. Decreased body-weight gain was noted at 320 mg/kg/day in both sexes as well as at the 80-mg/kg/day dose in females. Food consumption was decreased at all doses in males and at 80- and 320-mg/kg/day doses in females. Decreased erythrocyte parameters (erythrocyte count, hemoglobin and hematocrit) were observed in males receiving 320 mg/kg/day. Elevated urea nitrogen (BUN), increased kidney weight, decreased heart weight and exacerbation of chronic progressive nephropathy (CPN) severity were all observed in males at 80 and 320 mg/kg/day. However, only an exacerbated incidence of CPN was observed in females at 320 mg/kg/day. All changes were reversed after the 6-week recovery period, except BUN and CPN. Based on these results, we concluded that a dose of 20 mg/kg/day was the no observed adverse effect level. The toxicity target organ was the kidney. Males were more affected than females.

Translational implications of novel findings in cancer cachexia

Cancer cachexia is a complex metabolic syndrome that manifests as a progressive wasting disorder. Recent findings have substantially improved our understanding of this unique entity shedding light on a potentially significant and overlooked morbidity in the form of cardiac functional changes that may occur in tandem with cachexia. Moreover, recent technological advances, such as with the application of metabolomic analysis, have yielded a better understanding of the metabolic changes that accompany this condition. Recent evidence from murine studies indicates that the skeletal muscle wasting in cancer cachexia may be accompanied by cardiac muscle wasting. This decreased heart weight is accompanied by functional cardiac changes, which are suggestive of congestive heart failure. In addition, metabolomic analysis of body fluids and tissues distinguishes cancer cachexia's unique metabolic fingerprint as a separate entity, different from healthy controls, tumor burden, caloric restriction, and aging. It also gives insight into the metabolic changes that occur in the affected tissues such as the Warburg effect that is not often described in muscle. Translational investigations into potential cardiac malfunction in cancer patients and metabolomic analyses of patients' sera and tissues are warranted to determine whether these changes are upheld in humans.

Protective effect of Hypericum hircinum on doxorubicin-induced cardiotoxicity in rats

Oxidative stress is the main factor in doxorubicin (DOX) induced cardiotoxicity. Wistar rats received either DOX (3 mg kg−1, i.p.) every other day or combination of Hypericum hircinum (100 and 200 mg kg−1, p.o.) and DOX or H. hircinum (200 mg kg−1, p.o.) extract alone for 2 weeks. Cardiotoxicity was assessed by recording changes in ECG, heart rate and measuring the levels of cardiac marker enzymes – lactic acid dehydrogenase, creatine phosphokinase, glutamic oxaloacetic transaminase, the antioxidant defence enzymes – reduced glutathione (GSH), superoxide dismutase (SOD) and lipid peroxidative value (LPO) at the end of treatment schedule. Treatment with H. hircinum significantly (p < 0.05) decreased the levels of LPO and marker enzymes, increased the levels of GSH and SOD, reversed the changes in ECG and prevented the decrease in heart weight in DOX-treated group. The results suggest that H. hircinum has the potential to prevent the cardiotoxic effects induced by DOX.

Abstract 194: Increasing Expression of Connexin43 in Bone Marrow Stem Cells Enhances Their Protective Effects on the Infarcted Heart

Introduction: Coupling of stem cells (SCs) injected into the infarcted heart to endogenous cells that survived injury may enhance SC survival and engraftment and improve their protective effects. Connexin43 (Cx43) gap junctions are some of the first proteins expressed by differentiating SCs transplanted into the heart after myocardial infarction (MI), suggesting that cell coupling is critical for SC survival and differentiation. Hypothesis: Overexpression of Cx43 in SCs will enhance their ability to engraft, differentiate, and improve cardiac function and survival after transplant into the infarcted heart. Methods: Adult mouse SCs isolated from compact bone were sorted for c-kit surface marker using magnetic beads. SCs were transduced with PLL3.7 lentivirus encoding the Cx43 gene (GJA1) at MOI=300 to produce overexpression, which was confirmed by Western analysis on SC lysates. MI was induced in 12-week-old male C57BL/6 mice by ligating the left anterior descending coronary artery, and 40,000 SCs in 20 uL saline were administered immediately after MI via intramyocardial injection. A total of 69 animals were used: 18 received Cx43 SCs, 30 received non-transduced SCs (NTSC), 11 received only saline, and 10 underwent sham surgery. Echocardiography was performed 1 and 2 weeks post-MI. Results: Animals receiving Cx43 SCs had improved survival (90.0%) versus NTSC (76.7%) and saline controls (70.0%). The Cx43 SC group displayed improved ejection fraction versus NTSC and saline controls at 1 week (48.7% v. 43.3%, p=0.04; 30.1%, p&lt;0.0001) and 2 weeks post-MI (45.7% v. 40.4%, p=0.08; 26.8%, p=0.0004). Similar improvements in fractional shortening, stroke volume, and cardiac output were observed. Administration of Cx43 SC and NTSC attenuated remodeling with no difference between the two groups. Both decreased end-diastolic and systolic volumes, increased thickness of the infarct-related anterior wall, and decreased heart weight (HW), HW/body weight and HW/tibia length ratios at 1 and 2 weeks post-MI. Conclusion: All SCs improved survival and cardiac function, and attenuated remodeling. Transplantation of Cx43 SCs improved survival and cardiac function even more than NTSCs, suggesting that Cx43 may play a crucial role in engraftment and differentiation.

Subacute Therapeutic Dosing of Artemether-Lumefantrine and Artesunate-Amodiaquine Combination Preserves Plasma Cholesterol, Renal Antioxidant Status, and Organ Weights in Rats

Recent instances of breakdowns of malaria control programs and the constant emergence of drug-resistant parasites to monotherapies have shored up the use of artemisinin-based combination therapy (ACT) as the malaria therapy of choice. We evaluated a subacute therapeutic dosing of artemether-lumefantrine and artesunate-amodiaquine on plasma cholesterol, renal antioxidants, and organ weights in rats. Sixteen albino rats were grouped into three. Group A (n = 5) served as the control. Groups B (n = 6) and C (n = 5) were administered, twice daily, oral therapeutic doses of artemether-lumefantrine (1.14/6.86 mg/kg/d) and artesunate-amodiaquine (2.86/8.58 mg/kg/d), respectively, for seven days. From our results, ACTs did not significantly (P > 0.05) alter catalase, superoxide dismutase, glutathione S-transferase, myeloperoxidase, and total glutathione levels when compared with the control. Plasma total cholesterol levels also decreased insignificantly (P > 0.05). Organ-system weights were not significantly (P > 0.05) different from control rats. Artesunate-amodiaquine, but not artemether-lumefantrine, significantly increased (P < 0.05) lactate dehydrogenase activity and also afforded a 27.2% decrease in heart weight when compared with control. Also, both ACTs increased (P < 0.05) lipid peroxidation. Overall, artesunate-amodiaquine and artemether-lumefantrine may preserve renal antioxidants and organ weights in vivo. However, caution is required above therapeutic indications or in chronic doses as this may predispose to renal oxidative stress.

Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) Attenuates Interleukin-6 (IL-6)-induced Collagen Synthesis and Resultant Hypertrophy in Rat Heart

IL-6 has been shown to play a major role in collagen up-regulation process during cardiac hypertrophy, although the precise mechanism is still not known. In this study we have analyzed the mechanism by which IL-6 modulates cardiac hypertrophy. For the in vitro model, IL-6-treated cultured cardiac fibroblasts were used, whereas the in vivo cardiac hypertrophy model was generated by renal artery ligation in adult male Wistar rats (Rattus norvegicus). During induction of hypertrophy, increased phosphorylation of STAT1, STAT3, MAPK, and ERK proteins was observed both in vitro and in vivo. Treatment of fibroblasts with specific inhibitors for STAT1 (fludarabine, 50 μM), STAT3 (S31-201, 10 μM), p38 MAPK (SB203580, 10 μM), and ERK1/2 (U0126, 10 μM) resulted in down-regulation of IL-6-induced phosphorylation of specific proteins; however, only S31-201 and SB203580 inhibited collagen biosynthesis. In ligated rats in vivo, only STAT3 inhibitors resulted in significant decrease in collagen synthesis and hypertrophy markers such as atrial natriuretic factor and β-myosin heavy chain. In addition, decreased heart weight to body weight ratio and improved cardiac function as measured by echocardiography was evident in animals treated with STAT3 inhibitor or siRNA. Compared with IL-6 neutralization, more pronounced down-regulation of collagen synthesis and regression of hypertrophy was observed with STAT3 inhibition, suggesting that STAT3 is the major downstream signaling molecule and a potential therapeutic target for cardiac hypertrophy.

Abstract P058: Necessity of mTOR Inhibition and Autophagy Induction for Maintaining Cardiac Homeostasis During Caloric Restriction

Caloric restriction (CR) is a robust dietary intervention known to delay age-related heart disease. CR is able to antagonize cardiac remodeling in animal and human under various pathological conditions. However, the direct effect of CR on the heart at basal physiological state is not well characterized. In this study, we examined the impact of CR on cardiac homeostasis and explored the signaling mechanisms that mediate the cardiac effect of CR. Male C57BL/6J mice underwent 20% CR, i.e. 20% less food than ad libitum (AL), for 2 weeks and 40% CR for another 2 weeks. This CR regimen caused a roughly 20% decrease in heart weight and myocyte cross-sectional area. CR diminished the activity of the mammalian target of rapamycin ( mTOR) and accelerated autophagic flux. To determine the functional role of mTOR inhibition in CR-induced heart size reduction, we used transgenic mice that express a constitutively active mTOR (mTORca) in the heart. CR did not inhibit cardiac mTOR signaling in mTORca mice as it did in wild type (WT) mice. As a result, the ability of CR to reduce heart size in WT mice was severely impaired in mTORca mice. Specifically, CR reduced the heart weight by 23.1% in WT mice (p&lt;0.01 vs AL), but only tended to reduce it in mTORca mice (13.1%, p&gt;0.05 vs AL). Strikingly, when animals were treated with the mTOR inhibitor rapamycin, CR decreased heart weight in both WT and mTORca mice to the same extent, strongly suggesting that mTOR inhibition is required for CR to exert its cardiac effect. Autophagy is a cellular degradation pathway that may contribute to CR-induced heart size reduction. Surprisingly, CR can still decrease heart weight in 2 different autophagy-deficient mouse models, namely, beclin 1 heterozygous knockout mice and ATG16L1 hypomorphic mice. Nonetheless, cardiac function in these mice was markedly deteriorated during CR as indicated by decreased fractional shortening (Beclin 1+−: AL 37.9±2.8 vs CR 29.6±2.1, p&lt;0.01; ATG16L1-HM: AL 36.8±1.8 vs CR 30.1±2.1, p&lt;0.05). This was accompanied by increased oxidative injury, suggesting that autophagy is indispensible for a normal cardiac function during CR. In conclusion, both mTOR inhibition and autophagy induction are essential for maintaining cardiac homeostasis in response to CR-triggered mild stress.

FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model

The transcription factor FoxO3 contributes to anti-hypertrophic signalling in the heart presumably by regulating autophagic-lysosomal and ubiquitin-proteasomal pathways. We wanted to study FoxO3 function in the adult heart in vivo by expressing a constitutively active mutant of FoxO3 in transgenic mice. We generated transgenic mice in which a tetracycline-regulated constitutively active FoxO3 transgene (FoxO3-CA) is controlled by the heart-specific α-myosin heavy chain promoter. Cardiac-specific expression in adult mice resulted in a decrease in heart weight by 25% and a reduction in stroke volume and cardiac output. The decrease in heart size was due to a reduction in the size of individual cardiomyocytes, whereas there was no evidence for increased cell death. FoxO3 activation was accompanied by the initiation of a foetal gene programme with increased expression of β-myosin heavy chain and natriuretic peptides, and by the activation of AKT and mammalian target of rapamycin signalling. As shown by electron microscopy, FoxO3-CA massively stimulated destruction of sarcomeres and autophagy, and induced expression of LC3-II and BNIP3. When FoxO3-CA expression was shut off in affected mice, cardiac atrophy and dysfunction as well as molecular markers were normalized within 1 month. FoxO3-CA expression did not counteract hypertrophy induced by transverse aortic constriction. Heart-specific expression of constitutively active FoxO3 leads to reversible heart atrophy. The reversibility of the phenotype suggests a remarkable ability of the adult myocardium to respond to different regulatory cues.

Insulin-like growth factor-1 restores dexamethasone-induced heart growth arrest in rats: the role of the ubiquitin pathway

In skeletal muscle, glucocorticoids induce catabolism and proteolysis which is accomplished via the ubiquitin (Ub) proteolytic pathway. Cardiac muscle is a striated muscle which, compared to skeletal muscle, more abundantly expresses components of the Ub pathway, thus suggesting an important role for this pathway in heart physiology. The aim of our study was to explore the role of the Ub pathway in heart muscle physiology. We treated rats for three days with a pharmacologic dose of dexamethasone (DEXA) 0.5mg/100g body weight (BW). An attempt was also made to counteract the DEXA effect by co-treatment with insulin-like growth factor-1 (IGF-1; 0.35 mg/100g BW). DEXA treatment caused a 7.8% decrease in heart weight compared to control (p<0.05) and also increased heart tissue levels of the ubiquitin-conjugating enzyme E2 and the 20S proteasome protein. Myofibrillar proteins degraded by the ubiquitin pathway (α-actin, myoglobin, and troponin 1) were all decreased by DEXA, while ubiquitinated forms of α-actin were increased. Co-treatment with IGF-1 completely prevented DEXA-induced decrease in heart weight, an effect which was accompanied by decreased heart tissue levels of several ubiquitinated proteins including α-actin, the 20S proteasome protein, E2-14 kDa mRNA, and C-3 proteasome subunit mRNA, while the levels of non-ubiquinated α-actin, myoglobin, and troponin 1 were all partially restored. These results demonstrate that DEXA activates the ubiquitin proteolytic pathway in the heart and that IGF-1 efficiently counteracts this effect. Our findings reveal a possible mechanism for the anti-proteolytic actions of IGF-1 and its cardioprotective role involving the Ub pathway.

Effects of Coenzyme Q10 on Growth Performance and Heart Mitochondrial Function of Broilers Under High Altitude Induced Hypoxia

In order to test whether exogenous coenzyme Q10 (CoQ10) can improve growth performance and heart mitochondrial function of broilers grown at high altitude, a study was conducted on a farm in Xining City of Qinghai Province of China at an altitude of 2,200m with a 78% of partial pressure of atmospheric oxygen (O2) as compared to that at sea level. Three hundred, 1-d-old male, broilers (Arbor Acres) were divided into three groups and fed diets supplemented with 0mg (control, C), 20mg (Q1) or 40mg (Q2) CoQ10 per kg feed. CoQ10 supplementation increased body weight (BW) of broilers at 21d of age. BWs of Q1 (551.6±9.8g) and Q2 (509.4±10.7g) were higher than that of C (465.7±10.3g) at 21d of age (P<0.05). At 42d of age, BW of Q1 (2047.5±40.8g) was higher than that of C (1895.9±39.0g; P<0.05). Supplementation with CoQ10 decreased heart weight as a percentage of total BW (P<0.05) and improved yield (% BW) of breast muscle (P<0.05) as compared to C. Supplementation with CoQ10 at 40mg/kg feed decreased drip loss of breast muscle (P<0.05). Oxygen consumption of state III respiration and succinate-CoQ oxidoreductase (complex II) activity of heart mitochondria were increased by supplementation of CoQ10 (P<0.05). Supplemental CoQ10 at 40mg/kg feed increased state IV respiration rate (P<0.05). There was no significant difference in respiration control rate of heart mitochondria among the three treatment groups. Supplementation with CoQ10 at 20mg/kg increased glutathione peroxidase activity (P<0.05), and concomitantly decreased (P<0.05) the content of malondialdehyde in serum of 35-d old broilers. These findings suggest that CoQ10 can be used as a growth promoter in broilers at high altitude.

Antisense Inhibition of S6 Kinase 1 Produces Improved Glucose Tolerance and Is Well Tolerated for 4 Weeks of Treatment in Rats

p70 ribosomal S6 kinase 1 (S6K1) is implicated in the pathogenesis of type 2 diabetes as knockout mice are hypoinsulinemic, hypersensitive to insulin treatment and are less susceptible to obesity-induced insulin resistance. Although S6K1 knockout mice provide important information on the biology of this target, the therapeutic relevance of S6K1 inhibition in adult animals is unknown. Thus, this research evaluated the potential safety and efficacy of S6K1 inhibition using antisense oligonucleotides (ASO) in mature Sprague-Dawley rats. Male rats treated with S6K1 ASO (25 or 50 mg/kg, 2×/week × 4 weeks) had a marked reduction (>90%) of S6K1 mRNA in the liver and epididymal fat and no effect on hepatic S6K2 expression. The decrease in S6K1 mRNA translated to decreased (>80%) S6K1 protein and kinase activity in the liver at the 50-mg/kg dose. The animals tolerated the S6K1 treatment well with no signs of clinical toxicity. A reduction in body weight gain was observed within 2 weeks of S6K1 ASO treatment. At 4 weeks, body weight gain was reduced by up to 25% in the 50 mg/kg group with a commensurate decrease (14%) in food consumption. A decrease in heart weight in the 50 mg/kg group was observed and not associated with cardiac injury or dysfunction. In an oral glucose tolerance test, S6K1-ASO-treated animals demonstrated a dose-dependent improvement in systemic glucose utilization and had reduced fasting insulin levels. Hepatic gene microarray analysis identified dose-dependent elevations in igfbp1, acss2 and acat2 gene expression in S6K1-ASO-treated animals. These results suggest that inhibition of S6K1 for up to 4 weeks may be therapeutically relevant to induce insulin sensitization and attenuate weight gain with low risk for serious toxicity.

Cardioprotective effect of Sida rhomboidea. Roxb extract against isoproterenol induced myocardial necrosis in rats

The present study investigates cardioprotective effect of Sida rhomboidea. Roxb (SR) extract on heart weight, plasma lipid profile, plasma marker enzymes, lipid peroxidation, endogenous enzymatic and non-enzymatic antioxidants and membrane bound ATPases against isoproterenol (IP) induced myocardial necrosis (MN) in rats. Rats treated with IP (85 mg/kg, s.c.) recorded significant ( p<0.05) increment in heart weight, plasma lipid profile, plasma marker enzymes of cardiac damage, cardiac lipid peroxidation (LPO) and activity levels of Ca +2 ATPase whereas there was significant ( p<0.05) decrease in plasma HDL, cardiac endogenous enzymatic and non-enzymatic antioxidants, Na +–K + ATPase and Mg +2 ATPase. Pre-treatment with SR extract (400 mg/kg per day, p.o.) for 30 consecutive days followed by IP injections on days 29th and 30th, showed significant ( p<0.05) decrease in heart weight, plasma lipid profile, plasma marker enzymes of cardiac damage, cardiac lipid peroxidation, Ca +2 ATPase and significant increase in plasma HDL, cardiac endogenous enzymatic and non-enzymatic antioxidants, Na +–K + ATPase and Mg +2 ATPase compared to IP treated group. Hence, this study is the first scientific report on cardioprotective effect of SR against IP induced MN in rats.

Morphologic Features of Exertional Versus Nonexertional Sudden Death in Patients With Hypertrophic Cardiomyopathy

Pathologic features that characterize hypertrophic cardiomyopathy (HC) in exertional versus nonexertional sudden deaths have not been extensively studied. We performed gross measurements and histologic analysis on 103 autopsy cases of HC and correlated these with clinical findings. Pathologic features of the 71 sudden deaths were compared between exertional and nonexertional deaths. Age at death was significantly younger in exertional (27 +/- 13 years) versus nonexertional sudden deaths (40 +/- 16 years, p = 0.0003). Exertional deaths were more likely in women (35 of 37) versus sudden deaths at rest (21 of 34, p = 0.0002). There was no significant difference in the incidence of syncope in the exertional sudden deaths (14%) compared to the nonexertional sudden deaths (9%, p = 0.5) or in the rate of a previous diagnosis of HC (21% vs 21%, respectively). Mean heart weight was significantly decreased in exertional sudden deaths versus nonexertional sudden deaths. There was no difference in the frequency of left ventricular outflow tract plaque (54% exertional vs 46% nonexertional, p = 0.06). By multivariate analysis, including all categories of HC, only decreased heart weight (p = 0.02) and male gender (p = 0.002) were significantly associated with exertional sudden death. In conclusion, there are no pathologic features that would identify patients with HC at risk for exertional death. Because relatively decreased heart weight is strongly associated with exertional death, and because a large proportion of exertional deaths with HC are not associated with significant asymmetry, cardiologists should be careful in excluding the diagnosis of HC in athletes with even mild degrees of cardiomegaly, especially young men.

Cardiac anti‐remodelling effect of aerobic training is associated with a reduction in the calcineurin/NFAT signalling pathway in heart failure mice

Cardiomyocyte hypertrophy occurs in response to a variety of physiological and pathological stimuli. While pathological hypertrophy in heart failure is usually coupled with depressed contractile function, physiological hypertrophy associates with increased contractility. In the present study, we explored whether 8 weeks of moderate intensity exercise training would lead to a cardiac anti-remodelling effect in an experimental model of heart failure associated with a deactivation of a pathological (calcineurin/NFAT, CaMKII/HDAC) or activation of a physiological (Akt-mTOR) hypertrophy signalling pathway. The cardiac dysfunction, exercise intolerance, left ventricle dilatation, increased heart weight and cardiomyocyte hypertrophy from mice lacking alpha(2A) and alpha(2C) adrenoceptors (alpha(2A)/alpha(2C)ARKO mice) were associated with sympathetic hyperactivity induced heart failure. The relative contribution of Ca(2+)-calmodulin high-affinity (calcineurin/NFAT) and low-affinity (CaMKII/HDAC) targets to pathological hypertrophy of alpha(2A)/alpha(2C)ARKO mice was verified. While nuclear calcineurin B, NFATc3 and GATA-4 translocation were significantly increased in alpha(2A)/alpha(2C)ARKO mice, no changes were observed in CaMKII/HDAC activation. As expected, cyclosporine treatment decreased nuclear translocation of calcineurin/NFAT in alpha(2A)/alpha(2C)ARKO mice, which was associated with improved ventricular function and a pronounced anti-remodelling effect. The Akt/mTOR signalling pathway was not activated in alpha(2A)/alpha(2C)ARKO mice. Exercise training improved cardiac function and exercise capacity in alpha(2A)/alpha(2C)ARKO mice and decreased heart weight and cardiomyocyte width paralleled by diminished nuclear NFATc3 and GATA-4 translocation as well as GATA-4 expression levels. When combined, these findings support the notion that deactivation of calcineurin/NFAT pathway-induced pathological hypertrophy is a preferential mechanism by which exercise training leads to the cardiac anti-remodelling effect in heart failure.

Eplerenone Decreases Inflammatory Foci in Spontaneously Hypertensive Rat Hearts With Minimal Effects on Blood Pressure

The blood pressure (BP)-lowering effects of mineralocorticoid receptor (MR) antagonists in salt-sensitive rat models of hypertension are well understood. However, studies in salt-independent models have yielded mixed results, and therefore, we measured the hemodynamic effects of MR blockade in spontaneously hypertensive rats. We treated spontaneously hypertensive rats for 8 weeks with 30-300 mg.kg.d eplerenone or 20 mg.kg.d losartan and monitored BP using radiotelemetry and performed histopathological analyses of the hearts. Eplerenone, in contrast to losartan, caused only a small reduction in systolic BP at the highest dose tested. Both reduced left ventricular wall thickness, although eplerenone was less effective than losartan. Only losartan decreased heart weight. We observed foci of cardiomyopathy characterized by combinations of infiltrating monocytes, necrotic myocytes, and interstitial fibrosis in hearts of control animals. The number of foci seemed to be decreased in hearts of losartan- and eplerenone-treated animals. In a second study, using quantitative histomorphometry, the number of foci was significantly reduced by 20 mg.kg.d losartan (by 68%) or by 300 mg.kg.d eplerenone (by 50%). Our data support the hypothesis that a direct BP-independent effect on the progression of cardiomyopathy in the heart may be one basis for the cardiac protection afforded by MR antagonism.

Effect of Green Tea and Vitamin E Combination in Isoproterenol Induced Myocardial Infarction in Rats

The present study was aimed to investigate the combined effects of green tea and vitamin E on heart weight, body weight, serum marker enzymes, lipid peroxidation, endogenous antioxidants and membrane bound ATPases in isoproterenol (ISO)-induced myocardial infarction in rats. Adult male albino rats, treated with ISO (200 mg/kg, s.c.) for 2 days at an interval of 24 h caused a significant (P<0.05) elevation of heart weight, serum marker enzymes, lipid peroxidation and Ca+2 ATPase level whereas there was a significant (P<0.05) decrease in body weight, endogenous antioxidants, Na+/ K+ ATPase and Mg+2 ATPase levels. Administration of green tea (100 mg/kg/day, p.o.) and vitamin E (100 mg/kg/day, p.o.) together for 30 consecutive days and challenged with ISO on the day 29th and 30th, showed a significant (P<0.05) decrease in heart weight, serum marker enzymes, lipid peroxidation, Ca+2 ATPase and a significant increase in the body weight, endogenous antioxidants, Na+/K+ ATPase and Mg+2 ATPase when compared with ISO treated group and green tea or vitamin E alone treated groups. These findings indicate the synergistic protective effect of green tea and vitamin E during ISO induced myocardial infarction in rats.

Abstract 5417: Inducible 20S β Subunit LMP-2 is Down-Regulated in db/db Mouse Hearts with Diabetic Cardiomyopathy

Background: The ubiquitin-proteasome system (UPS) plays an important role in cell growth, differentiation, and survival. Low molecular mass polypeptide (LMP)-2 is an inducible 20S beta subunit and its role in diabetic cardiomyopathy has not been previously studied. We investigated the hypothesis that LMP-2 is down-regulated in diabetic hearts and is involved in diabetic cardiomyopathy. Methods: db/db mice and control db/+ littermates were studied at 20 weeks of age. Cardiac function was measured by echocardiography. Chymotryptic-like activity of the 20S proteasome was analyzed by fluorogenic assay using the substrate Suc-LLVY-aminomethycoumarin (-AMC). Results: db/db mice had a severe increase in blood glucose and a decrease in heart weight compared with db/+ mice (135±6 vs. 168±7 mg, n = 4, p &lt; 0.01). Left ventricular function was decreased with a lower fractional shortening in db/db mice (48.7±3.2 vs. 60.7±0.4 %, n = 4, p &lt; 0.05). LMP-2 was constitutively expressed in both db/+ and db/db mouse hearts, but its level was severely depressed in the db/db hearts (78±11 vs. 245±18 AU, n = 4, p &lt; 0.01). Consistent with the change in LMP-2, chymotryptic-like activity was also significantly down-regulated in these diabetic hearts (3286±112 vs. 3598±52 AU, n = 3, p &lt; 0.05). Furthermore, the role of LMP-2 in regulating 20S proteasome function and cardiac mass was determined in LMP-2 knockout and wildtype mice. Chymotryptic-like activity was significantly decreased in LMP-2 knockout mouse hearts (11156±360 vs. 18280±454 AU, n = 4, p &lt; 0.01), and cardiac atrophy was found in these knockout mice (147±7.1 vs 178±10.5 mg, n=10; p &lt; 0.01). Taken together, these results suggest that LMP-2 is necessary for normal proteasome function in the heart and its down-regulation may contribute to the development of diabetic cardiomyopathy.

Cardiac angiotensin receptor expression in hypothyroidism: back to fetal gene programme?

Cardiac angiotensin receptor expression in hypothyroidism: back to fetal gene programme?