Significant Increase In Heart Weight Research Articles

Vps4a Regulates Autophagic Flux to Prevent Hypertrophic Cardiomyopathy.

Autophagy has stabilizing functions for cardiomyocytes. Recent studies indicate that an impairment in the autophagy pathway can seriously affect morphology and function, potentially leading to heart failure. However, the role and the underlying mechanism of the endosomal sorting complex required for transport (ESCRT) family protein, in particular the AAA-ATPase vacuolar protein sorting 4a (Vps4a), in regulating myocardial autophagy remains unclear. In the present study, cardiomyocyte-specific Vps4a knockout mice were generated by crossing Vps4aflox/flox (Vps4afl/fl) with Myh6-cre transgenic mice. As a result, we observed a partially dilated left ventricular (LV) chamber, a significant increase in heart weight to body weight ratio (HW/BW), and heart weight to tibial length ratio (HW/TL), hypertrophic cardiomyopathy and early lethality starting at 3 months of age. Hematoxylin-eosin (HE), immunofluorescence assay (IFA), and Western blot (WB) revealed autophagosome accumulation in cardiomyocytes. A transcriptome-based analysis and autophagic flux tracking by AAV-RFP-GFP-LC3 showed that the autophagic flux was blocked in Vps4a knockout cardiomyocytes. In addition, we provided in vitro evidence demonstrating that Vps4a and LC3 were partially co-localized in cardiomyocytes, and the knockdown of Vps4a led to the accumulation of autophagosomes in cardiomyocytes. Similarly, the transfection of cardiomyocytes with adenovirus (Adv) mCherry-GFP-LC3 further indicated that the autophagic flux was blocked in cells with deficient levels of Vps4a. Finally, an electron microscope (EM) showed that the compromised sealing of autophagosome blocked the autophagic flux in Vps4a-depleted cardiomyocytes. These findings revealed that Vps4a contributed to the sealing of autophagosomes in cardiomyocytes. Therefore, we demonstrated that Vps4a deletion could block the autophagic flux, leading to the accumulation of degradation substances and compromised cardiac function. Overall, this study provides insights into a new theoretical basis for which autophagy may represent a therapeutic target for cardiovascular diseases.

Long-term Dexamethasone Treatment Increases Cardiac Galectin-3 Levels.

Glucocorticoids, which are widely prescribed around the world, cause cardiac remodeling in long-term treatment by triggering insulin resistance and increasing blood pressure. However, its role in cardiac remodeling remains unclear. Galectin-3 (gal-3) is a member of a beta-galactoside-binding animal lectins, upregulated as a result of insulin resistance and in the pressure-overloaded myocardium and regulate cardiac remodeling. We hypothesized that gal-3 may be upregulated in the myocardium with prolonged use of glucocorticoids and associated with cardiac hypertrophy. To examine the involvement of glucocorticoids in gal-3 levels in rat myocardium, sixteen female Wistar Albino rats were assigned to control (C; n = 8) and dexamethasone (Dex; n = 8) groups. Daily dexamethasone was injected subcutaneously for 28days at a dose of 1mg.kg-1. Control animals were injected with the same volume of saline. The body weight and heart weights were determined. Gal-3 levels in myocardium were determined by Western blot. Our data shows that dexamethasone administration resulted in significant increase in heart weight (p < 0.05) and HW/BW ratios (p < 0.001) and 28days of dexamethasone administration with the dose of 1mg.kg-1 caused a twofold increase in the gal-3 expression in the left ventricle (p < 0.001). The finding of the current study is the first to show that dexamethasone causes an increase in gal-3 levels in myocardium. Our study provides an important step in the development of possible therapeutics by determining that dexamethasone causes an increase in gal-3 levels in the myocardium and raises awareness about the follow-up of patients receiving long-term glucocorticoid therapy.

Effects of SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone on fluid retention in type 2 diabetic mice with NASH

Several antidiabetic agents, including thiazolidinediones and sodium-glucose cotransporter (SGLT) 2 inhibitors, attenuate the symptoms of nonalcoholic steatohepatitis (NASH). However, thiazolidinediones have serious side effects such as fluid retention and increased risk of congestive heart failure. We examined the effects of SGLT2 inhibitor ipragliflozin, pioglitazone, and ipragliflozin + pioglitazone on fluid retention in type 2 diabetic mice with NASH. Four-week repeated administration of pioglitazone caused significant increases in heart weight (31% increase in 30 mg/kg pioglitazone-treated group compared to vehicle-treated group) concomitant with fluid retention, as estimated by a decrease in plasma osmolality and increase in water intake/urine volume ratio. In addition, pioglitazone significantly increased (by 1.5 to 2-fold) mRNA expression of α, β, and γ subtypes of ENaC and AQP2 and 3 subtypes in the renal medulla. Thus, pioglitazone-induced fluid retention may arise from enhanced reabsorption of sodium and water associated with increased expression of these channels in the kidney. In contrast, ipragliflozin alone did not induce these symptoms and did not affect ENaC or AQP expression. Combination treatment with ipragliflozin + pioglitazone attenuated these symptoms by ipragliflozin-induced osmotic diuresis. These findings demonstrate that treatment with ipragliflozin monotherapy or coadministered with pioglitazone may be a potential therapeutic option for the treatment of type 2 diabetes with NASH without fluid retention as a side effect.

Upregulated Angiogenesis Is Incompetent to Rescue Dilated Cardiomyopathy Phenotype in Mice.

Dilated cardiomyopathy (DCM) is characterized by pathologic cardiac remodeling resulting in chambers enlargement and impaired heart contractility. Previous reports and our in-silico analysis support the association of DCM phenotype and impaired tissue angiogenesis. Here, we explored whether the modulation in cardiac angiogenesis partly intervenes or rescues the DCM phenotype in mice. Here, a DCM mouse model [α-tropomyosin 54 (α-TM54) mutant] was crossbred with microRNA-210 transgenic mice (210-TG) to develop microRNA-210 (miR-210) overexpressing α-TM54 mutant mice (TMx210). Contrary to wild-type (WT) and 210-TG mice, a significant increase in heart weight to body weight ratio in aged mixed-gender TMx210 and DCM mice was recorded. Histopathological analysis revealed signs of pathological cardiac remodeling such as myocardial disarray, myofibrillar loss, and interstitial fibrosis in DCM and TMx210 mice. Contrary to WT and DCM, a significant increase in angiogenic potential was observed in TMx210 and 210-TG mice hearts which is reflected by higher blood vessel density and upregulated proangiogenic vascular endothelial growth factor-A. The echocardiographic assessment showed comparable cardiac dysfunction in DCM and TMx210 mice as compared to WT and 210-TG. Overall, the present study concludes that miR-210 mediated upregulated angiogenesis is not sufficient to rescue the DCM phenotype in mice.

Investigating Cardiac Morphological Alterations in a Pentylenetetrazol-Kindling Model of Epilepsy.

Epilepsy is a group of neurological disorders characterized by abnormal electrical activity in the central nervous system (CNS) and recurrent seizures representing the principal clinical manifestation. Sudden unexpected death in epilepsy (SUDEP) is the predominant cause of death in young epileptic patients. SUDEP patients displayed an increased cardiovascular (CV) risk, probably due to an impaired autonomic control of CV functions, but the underlying mechanisms need to be explored yet. Therefore, we aimed to examine the cardiac morphological alterations in a pentylenetetrazol (PTZ)-kindled rat model, a well-established tool for studying chronic epilepsy. To complete this, the distance between the atria, between the atrium and ventricle were measured, the heart was weighed, and the pathological morphology of dissected hearts was analyzed by histological assessment with hematoxylin and eosin staining. A significantly decreased distance between atria and a significant increase in heart weight were observed in PTZ-kindled rats which interestingly also displayed increased hemorrhagic content when compared with controls. Our findings provided evidence that changes in cardiac morphology may be related to autonomic CV dysfunctions occurring during SUDEP while also opening up more avenues to better develop novel drugs for the treatment of this disorder.

Morphological and histopathological evaluation of autopsied patients with hypertensive cardiopathy

BackgroundPhysiopathological processes in hypertensive heart disease are controlled by complex interactions between cardiomyocytes, extracellular matrix, microvasculature and other cells present in the myocardium. ObjectiveTo analyze morphological changes in hypertensive cardiopathy and to describe and compare findings in order to help clarify determinant factors. Methods42 fragments of the left ventricular myocardium and circumflex branch of the left coronary artery were obtained from individuals autopsied at the Clinical Hospital of the Federal University of Triângulo Mineiro (UFTM) in the period ranging from 1984 to 2018. Groups were split into individuals with hypertensive heart disease (HD) and individuals without heart disease (ND). Wall thickness was measured with a digital caliper and Computed Tomography. Quantification of collagen fibers was conducted by computerized morphometry and mast cell density was assessed by immunohistochemical methods. ResultsThere was a significant increase of heart weight in the HD group compared to the ND group, (p = 0.0002). There was a significant increase of thickness of the middle third of the free wall in the HD group compared to the ND group, (p = 0.04). There was a significant increase of collagen fibers in the left ventricle in the HD group compared to the ND group, (p < 0.0001). Concerning mast cell density, there was a significant increase in the left ventricle of individuals with HD immuno-labeled by the set anti-chymase/anti-tryptase (p < 0.0001). There was a significant increase of mast cell density in the circumflex branch of the left coronary artery of individuals with HD immuno-labeled by the set anti-chymase/anti-tryptase (p = 0.01). ConclusionsMast cells are involved in the development of hypertensive heart disease, contributing to the remodeling of collagen fibers in this disease.

Carotid-Jugular Fistula Model to Study Systemic Effects and Fistula-Related Microcirculatory Changes

Background: Arteriovenous fistulae impair the distal circulation, but their effects at the microcirculatory level are not well understood. This study presents the carotid-jugular fistula (CJF) as a model to evaluate fistula-related microcirculatory and systemic changes. Materials and Methods: Female Wistar rats were anesthetized and divided into a fistula group (FG, n = 10) and a sham group (SG, n = 6). End-to-end anastomosis was performed between the right carotid artery and the jugular vein in the FG. The hemodynamic status was followed for 6 weeks. On the sixth postoperative week, liver and kidney microcirculation was measured using laser Doppler; then microcirculatory changes were assessed after occlusion of the carotid artery. At the end of the experiment, histological samples were taken and the weights of the organs were measured. Results: The heart rate and systolic blood pressure decreased significantly due to the CJF. Laser Doppler showed a reduction in liver blood flow units (BFU) in the FG in comparison with the SG (p = 0.01), and they increased (p < 0.01) after occlusion of the fistula. Kidney BFU showed slight changes only. The comparative morphological study revealed significant increases in heart weight (p < 0.001) and left ventricular hypertrophy (p = 0.008) in the FG. Conclusion: Beside hemodynamic and morphologic changes, a CJF causes a deterioration in the microcirculation of the liver rather than of the kidney, but occlusion of the CJF immediately reverses these changes.

322: Effects of selective reduced uterine perfusion pressure on organs commonly affected by preeclampsia

Selective reduced uterine perfusion pressure (SRUPP) has been used as a model of pregnancy related hypertensive disease in rats. In this study, we aimed to assess the effects of the SRUPP model on the weight of organs commonly affected by hypertensive disorders. 30 timed pregnant, Sprague-Dawley rats were divided into two groups, the SRUPP (n=30) or the control, sham surgery group (n=30). On gestational day 13 the rats underwent mean arterial pressure (MAP) analysis by tail cuff plethysmography. On gestational day 14, rats were anesthetized with 2% isoflurane and the abdomen entered through a midline vertical incision. Fetuses were counted, uterine and utero-ovarian arteries were identified and surgically isolated from the surrounding adipose tissue. In the SRUPP cohort, silver clips (0.102mm internal diameter) were placed on the aforementioned vessels bilaterally while the Sham surgery group vessels were solely isolated. The rats were returned to their home cages after surgery until gestational day 20 when MAP was again obtained. On day 21 the rats were terminally anesthetized with isoflurane. A second laparotomy was performed and organs of interest were harvested. Heart, kidney, mean fetal, and mean placental weights were obtained. Results are expressed in mean and standard error mean. Independent sample t-test was used for the statistical analysis. A two-sided p < 0.05 indicated a statistical significance. The heart weight was significantly greater in the SRUPP group when compared with controls (802.13 ± 32.804 vs 701.09 ± 19.548 mg; p= .012). There was no significant difference in the renal, mean fetal, or placental weight of SRUPP vs Control (See Table 1). SRUPP appears to be associated with a significant increase in heart weight. These changes suggest that in SRUPP the greater heart weight is a consequence of myocardial hypertrophy due to hypertension.

Inhibition of inducible nitric oxide synthase (iNOS) by simvastatin attenuates cardiac hypertrophy in rats.

The left ventricular hypertrophy (LVH) occurs in response to the haemodynamic overload in some physiological and pathological conditions. This study was designed to investigate the possible cardioprotective effect of simvastatin (SIM) treatment against isoproterenol (ISO)-induced LVH and the probable underlying mechanism in adult male Wistar rats. Animals were allocated into four groups. Rats of control group received normal saline orally for 30 days and intraperitoneally for the last 7 days. Rats of SIM group received SIM orally (10 mg/kg/day in saline) for 30 days. Rats of ISO group received normal saline orally for 30 days and ISO intraperitoneally (5 mg/kg) for the last 7 days to induce LVH. Rats of ISO/SIM group received SIM for 30 days and ISO intraperitoneally for the last 7 days. At the end of the experiment, all animals were sacrificed by cervical decapitation under anaesthesia. Truncal blood was collected and serum was separated and used for biochemical assay. The heart was dissected and processed for histological and immunohistochemical studies. The results of the present study confirmed the ISO-induced myocardial lesions including significant increase of heart weight (HW), heart weight/body weight (HW/BW) ratio, LVH, interstitial myocardial fibrosis (increased collagen types I and III), inflammatory cellular infiltration, necrosis of cardiomyocytes, and increased expression of inducible nitric oxide synthase (iNOS) and thioredoxin in cardiomyocytes. These changes were accompanied by significant increase in serum levels of troponin-T, creatine phosphokinase-MB (CPK-MB), tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Co-administration of SIM to ISO-injected rats significantly reduced all these cardiac changes and serum biochemical markers in addition to marked depletion of iNOS and thioredoxin expression in cardiomyocytes. It is concluded that SIM co-administration attenuated ISO-induced cardiac lesions including LVH by inhibiting iNOS expression in cardiomyocytes.

(-)-Epicatechin induces physiological cardiac growth by activation of the PI3K/Akt pathway in mice.

The flavanol (-)-epicatechin (Epi) has cardioprotective effects and improves physical capacity in normal mice. In addition, Epi increases nitric oxide (NO) production by activation of both PI3K/Akt or Ca2+ /CaMI/CaMKII (where Akt is protein kinase B; PI3K is phosphoinositide 3-kinase; CaMI is calmodulin; CaMKII is Ca2+ /calmodulin-dependent protein kinase II) signaling pathways, which have been associated with physiological and pathological cardiac hypertrophy, respectively. Notwithstanding all this information, few studies have been carried out that aimed to determine the potential beneficial effects that Epi may have in normal heart. Mice were treated by oral gavage with the flavanol Epi. The treatment induced a significant increase in heart weight, size of the free walls, and size of the cardiac fibers. Also, no evidence of cardiac fibrosis was revealed. Furthermore, the phosphorylation level of PI3K/Akt/mTOR/p70S6K (where mTOR is mammalian target of rapamycin; p70S6K is ribosomal protein S6 kinase beta-1) proteins was significantly higher in the heart of Epi-treated animals. In contrast, a significantly decreased level of pathological cardiac hypertrophy markers atrial natriuretic peptide and brain natriuretic peptide was observed along with no modification in the level of β myosin heavy chain beta, calmodulin, and Ca2+ /calmodulin-dependent protein kinase II proteins. Hemodynamic parameters indicated an improvement in mechanical heart performance after Epi treatment. Interestingly, morphometric parameters were similar between treated and untreated mice after 4 wk without treatment. These findings indicate that Epi treatment induced physiological cardiac growth in healthy mice by activation of the PI3K/Akt pathway.

0327 : Impact of a high fat diet on plasma and heart biochemical parameters of prepubertal male and female rabbits

The biochemical cardiac and plasmatic damages induced by high-fat diet were examined in male and female rabbit and compared to the control models. Experiments were carried on 24 pre-pubertal New Zealand white rabbits, 12 males and 12 females, randomized into 4 groups (for each, n=6), 2 control groups, male (MC) and female (FC) fed a normal fat diet, and 2 High Fat Diet groups (MHFD, FHFD). HFD contained 1g of peanut butter +0.5g of animal fat. Body and heart weights were compared between the groups. Glucose, total proteins, uric acid, TG, cholesterol, phosphorus and phospholipids were examined by enzymatic methods in the plasma. The total lipids extracted from heart (Folch, 1957) were analyzed by TLC. Results obtained with HFD are compared with those of standard diet. At the end of experiment, the results showed a modest raise of body weight among MHFD vs MC, but very significant among FHFD vs FC (p<0,0001), also a significant increase of heart weight among FHFD vs MHFD, and a small raise of glycemia among MHFD vs FHFD (p<0,05).With HFD, the levels of proteins, uric acid and HDL-C were similar between female and male. The cholesterol showed a small raise in both MHFD and FHFD vs controls (p<0,05). LDL-C increased very significantly among MHFD vs MC (p<0,0001) and among FHFD vs FC(p<0,0001).There was a small raise of phospholipids in both FHFD and MHFD (p<0,05), also a small raise of TG among FHFD vs MHFD(p<0,05).In the heart, there was a small raise of total lipids for both MHFD and FHFD vs controls (p<0,05), and a small raise of phosphorus among MHFD vs FHFD, also a little raise of proteins among FHFD vs MHFD (23,85±2,61 mg/g vs 19,98±0,46 mg/g of heart).The TLC showed an increase of lipid levels among MHFD vs MC, also among FHFD vs FC. Diet supplemented with peanut butter and animal fat is responsible for major metabolic alterations in the heart and plasma of pre-pubertal male and female rabbits. The author hereby declares no conflict of interest

Preservation of Cardiac Function and Attenuation of Remodelling in Transient Receptor Potential Vanilloid 4 Knockout Mice Following Myocardial Infarctionnd Medical Center

Transient receptor potential channel vanilloid 4 (TRPV4) is a non-selective Ca2+ permeable cation channel, recently implicated by computational methods as a key signalling component during myocardial infarction. We previously showed that pharmacological TRPV4 inhibition can prevent and resolve pulmonary edema in pre-clinical heart failure animal models. Here, we examined the impact of genetic deletion of TRPV4 (TRPV4-/-) on cardiac function, both basally and following myocardial infarction. Cardiac function was similar in wild type and TRPV4-/- mice under normal conditions. By contrast, following myocardial infarction induced by permanent ligation of the left anterior descending coronary artery, left ventricular systolic and diastolic volumes were reduced and ejection fraction was significantly improved in TRPV4-/- when compared to wild type mice. Consistent with the differences in chamber volumes between TRPV4-/- and wild type mice, myocardial infarction induced a significant increase in heart weight and left ventricular mass index in wild type, but not in TRPV4-/- mice. In a separate cohort of mice, we also investigated the effect of genetic deletion of TRPV4 on infarct size after a 30 min myocardial ischemia and 24 hours reperfusion. There were no differences in myocardial infarct size or area at risk in TRPV4-/- and wild type mice after ischemia/reperfusion injury. These results suggest that TRPV4 does not mediate acute myocardial ischemic injury, but does play an important role in ventricular remodelling known to correlate with poor outcomes following acute myocardial infarction.

Myocardial potency of Bio-tea against Isoproterenol induced myocardial damage in rats.

Kombucha (Bio-tea) is a beverage produced by the fermentation of sugared black tea using a symbiotic association of bacteria and yeasts. Traditional claims about Kombucha report beneficial effects such as antibiotic properties, gastric regulation, relief from joint rheumatism and positive influence on the cholesterol level, arteriosclerosis, diabetes, and aging problems. The present investigation was carried out to understand the preventive effect of Kombucha on heart weight, blood glucose, total protein, lipid profile and cardiac markers in rats with myocardial damage induced using Isoproterenol. As Bio-tea is produced by fermenting tea, the parameters were compared in rats pre-treated with normal black tea and Bio-tea for 30days followed by subcutaneous injection of Isoproterenol (85mg/kg body weight). Normal rats as well as Isoproterenol induced myocardial infarcted rats were also used, which served as controls. Isoproterenol induced myocardial infarcted control rats showed a significant increase in heart weight, blood glucose and cardiac markers and a decrease in plasma protein. Increased levels of cholesterol, triglycerides, low density lipids (LDL) and very low density lipids (VLDL) were also observed, while the high density lipid (HDL) content decreased. Bio-tea showed a higher preventive effect against myocardial infarction when compared to tea, as was observed by the significant reduction in heart weight, and blood glucose and increase in plasma albumin levels. Bio-tea significantly decreased cholesterol, triglycerides, LDL and VLDL while simultaneously increasing the levels of HDL. Similarly a decrease in leakage of cardiac markers from the myocardium was also observed.

A systems biology approach to understand the pathophysiological mechanisms of cardiac pathological hypertrophy associated with rosiglitazone.

BackgroundCardiac pathological hypertrophy is associated with a significantly increased risk of coronary heart disease and has been observed in diabetic patients treated with rosiglitazone whereas most published studies do not suggest a similar increase in risk of cardiovascular events in pioglitazone-treated diabetic subjects. This study sought to understand the pathophysiological and molecular mechanisms underlying the disparate cardiovascular effects of rosiglitazone and pioglitazone and yield knowledge as to the causative nature of rosiglitazone-associated cardiac hypertrophy.MethodsWe used a high-fat diet-induced pre-diabetic mouse model to allow bioinformatics analysis of the transcriptome of the heart of mice treated with rosiglitazone or pioglitazone.ResultsOur data show that rosiglitazone and pioglitazone both markedly improved systemic markers for glucose homeostasis, fasting plasma glucose and insulin, and the urinary excretion of albumin. Only rosiglitazone, but not pioglitazone, tended to increase atherosclerosis and induced pathological cardiac hypertrophy, based on a significant increase in heart weight and increased expression of the validated markers, ANP and BNP. Functional enrichment analysis of the rosiglitazone-specific cardiac gene expression suggests that a shift in cardiac energy metabolism, in particular decreased fatty acid oxidation toward increased glucose utilization as indicated by down regulation of relevant PPARα and PGC1α target genes. This underlies the rosiglitazone-associated pathological hypertrophic cardiac phenotype in the current study.ConclusionApplication of a systems biology approach uncovered a shift in energy metabolism by rosiglitazone that may impact cardiac pathological hypertrophy.

Abstract 159: Cardiac Hypertrophy and Sudden Death in a Mouse Model of STIM1 Overexpression

Background: STIM1, an ER/SR resident Ca 2+ sensing protein regulates Ca 2+ entry following internal Ca 2+ store depletion in a broad range of tissues and cell types. However their putative roles in excitable tissue such as cardiac myocytes is uncertain. Results: Here we generated a mouse model of STIM1 overexpression in cardiac and skeletal muscle. Western blot analysis suggested approximately 4-6 fold STIM1 overexpression in Tg mouse hearts compared to Ntg littermates. Immunocytochemistry carried out in ventricular myocytes revealed that STIM1 and the cardiac ryanodine receptor (RyR2) co-localize. Functionally, the amplitude of Ca 2+ entry following SR Ca 2+ depletion was 2-fold greater in myocytes isolated from STIM1 Tg mice compared to NTg littermates. Echocardiographic analysis in STIM1 Tg mice showed age dependent remodeling of the myocardium with a significant decrease in fractional shortening at 16 weeks of age (14.4.5±3.8 in STIM1 Tg vs. 36.9±1.5 in Ntg). These changes were accompanied by a significant increase in heart weight to tibia length (13.6 +/- 1.4 vs 6.5 +/- 0.24) and increased lung weight to tibia length ratio (11.6+/- 2.1 vs 8.1 +/- 0.38) in STIM1 Tg mice compared to Ntg littermates. Photometry experiments in isolated ventricular myocytes demonstrated significantly increased Ca 2+ transient amplitude with an unexpected decrease in the SR Ca 2+ load associated with STIM1 overexpression. In addition transgenic mice showed increased calcineurin-nuclear factor of activated T cells (NFAT) activation in vivo, increased CaMKII activity, interstitial fibrosis and exaggerated hypertrophy following two weeks of neuroendocrine agonist or pressure overload stimulation. Conclusion: Our observations suggest that STIM1 overexpression by itself can lead to cardiac hypertrophy and contribute to pathological cardiac remodeling and possibly sudden cardiac death. The molecular mechanisms underlying these phenomena are currently under investigation.

FKBP12.6 overexpression does not protect against remodelling after myocardial infarction

Reducing the open probability of the ryanodine receptor (RyR) has been proposed to have beneficial effects in heart failure. We investigated whether conditional FKBP12.6 overexpression at the time of myocardial infarction (MI) could improve cardiac remodelling and cell Ca(2+) handling. Wild-type (WT) mice and mice overexpressing FKBP12.6 (Tg) were studied on average 7.5 ± 0.2 weeks after MI and compared with sham-operated mice for in vivo, myocyte function and remodelling. At baseline, unloaded cell shortening in Tg was not different from WT. The [Ca(2+)](i) transient amplitude was similar, but sarcoplasmic reticulum (SR) Ca(2+) content was larger in Tg, suggesting reduced fractional release. Spontaneous spark frequency was similar despite the increased SR Ca(2+) content, consistent with a reduced RyR channel open probability in Tg. After MI, left ventricular dilatation and myocyte hypertrophy were present in both groups, but more pronounced in Tg. Cell shortening amplitude was unchanged with MI in WT, but increased with MI in Tg. The amplitude of the [Ca(2+)](i) transient was not affected by MI in either genotype, but time to peak was increased; this was most pronounced in Tg. The SR Ca(2+) content and Na(+)- Ca(2+) exchanger function were not affected by MI. Spontaneous spark frequency was increased significantly after MI in Tg, and larger than in WT (at 4 Hz, 2.6 ± 0.4 sparks (100 μm)(-1) s(-1) in Tg MI versus 1.6 ± 0.2 sparks (100 μm)(-1) s(-1) in WT MI; P < 0.05). We conclude that FKPB12.6 overexpression can effectively reduce RyR open probability with maintained cardiomyocyte contraction. However, this approach appears insufficient to prevent and reduce post-MI remodelling, indicating that additional pathways may need to be targeted.

Activated NHE1 is required to induce early cardiac hypertrophy in mice

The Na+/H+ exchanger isoform 1 (NHE1) has been implicated as being causal in cardiac hypertrophy and the protein level and activity are elevated in the diseased myocardium. However, it is unclear whether mere elevation of the protein is sufficient for cardiac pathology, or whether activation of the protein is required. In this study, we examined the comparative effects of elevation of wild type and activated NHE1. Two mouse transgenic models that expressed either a wild type NHE1 protein or an activated NHE1 protein were characterized. Expression of activated NHE1 caused significant increases in heart weight to body weight, apoptosis, cross-sectional area, interstitial fibrosis and decreased cardiac performance. Expression of wild type NHE1 caused a much milder pathology. When we examined 2 or 10-week-old mouse hearts, there was neither elevation of calcineurin levels nor increased phosphorylation of ERK or p38 in either NHE1 transgenic mouse line. Expression of activated NHE1 in intact mice caused an increased sensitivity to phenylephrine-induced hypertrophy. Our results show that expression of activated NHE1 promotes cardiac hypertrophy to a much greater degree than elevated levels of wild type NHE1 alone. In addition, expression of activated NHE1 promotes greater sensitivity to neurohormonal stimulation. The results suggest that activation of NHE1 is a key component that accentuates NHE1-induced myocardial pathology.

Insulin-Like Growth Factor-1 (IGF-1) Reduces ischemic changes and increases circulating angiogenic factors in experimentally - induced myocardial infarction in rats

BackgroundCoronary artery disease is a global health concern in the present day with limited therapies. Extensive efforts have been devoted to find molecular therapies to enhance perfusion and function of the ischemic myocardium. Aim of the present study was to look into the effects of insulin like growth factor -1 (IGF-1) on circulating angiogenic factors after myocardial ischemia in rats.MethodsAdult male Sprague-Dawley rats were randomly divided into 10-days control, myocardial infarction, IGF-1 alone (2 μg/rat/day) and ISO+IGF-1 groups. Isoproterenol (ISO), a synthetic catecholamine was used to induce myocardial infarction. Serum transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) levels were checked after 10-days of IGF-1 administration.ResultsThere was a significant increase in heart weight after IGF-1 treatment. A significant increase in cardiac enzyme level (CK-MB and LDH) was seen in isoproterenol treated rats when compared to control group. IGF-1treatment induced a significant increase in serum angiogenic factors, IGF-1, VEGF and TGF beta levels. IGF-1 also reduced the ischemic changes in the myocardium when compared to the isoproterenol alone treated group.ConclusionsIn conclusion, treatment with insulin-like growth factor-1 (IGF-1) in myocardial infarction significantly increased circulating angiogenic growth factors like IGF-1, VEGF and TGF beta thus, protecting against myocardial ischemia.

(—)-Epigallocatechin gallate (EGCG) prevents isoprenaline-induced cardiac toxicity by stabilizing cardiac marker enzymes and membrane-bound ATPases

Intake of tea flavonoids has been reported to reduce the incidence of cardiovascular disease. The present study was undertaken to investigate the preventive effect of (-)epigallocatechin gallate (EGCG) on heart weight, cardiac marker enzymes, membrane-bound ATPases and electrolytes in isoprenaline (ISO)-induced myocardial infarcted (MI) Wistar rats. Rats subcutaneously administered ISO 100 mgkg(-1) at intervals of 24 h for 2 days resulted in significant increases in heart weight and the activities of cardiac marker enzymes such as creatine kinase, creatine kinase-MB, lactate dehydrogenase (LDH), aspartate transaminase and alanine transaminase in serum, and significant decreases in the activities of these enzymes in the myocardium. ISO injection also increased levels of LDH isoenzymes (LDH 1 and LDH 2). The activity of Na+/K+ ATPase was decreased significantly and the activities of Ca2+ and Mg2+ ATPases were increased significantly in ISO-induced MI rats. Furthermore, the levels of potassium were lowered and the levels of sodium and calcium were increased in ISO-induced MI rats. Prior treatment with EGCG (10, 20 and 30 mgkg(-1)) daily for a period of 21 days reduced the effects of ISO on heart weight, activities of cardiac marker enzymes and membrane bound-ATPases and levels of LDH 1 and LDH 2 and electrolytes. Thus, EGCG exhibits beneficial effects on these enzymes and electrolytes. The observed effects may be due to the antioxidant and membrane-stabilizing effects of EGCG in ISO-induced MI rats.

The protective effects of taurine against renal damage by salt loading in Dahl salt-sensitive rats.

We evaluated whether taurine prevents renal damage which is accompanied with enhanced expression of lectin-like oxidized low-density lipoprotein (OxLDL) receptor-1 (LOX-1) mRNA, in salt-loaded Dahl salt-sensitive (DS) rats. Male, 4-week-old DS rats were fed on either a high-salt (8% NaCl) or normal-salt (0.66% NaCl) diet for 4 weeks. Some DS rats with high-salt diet were given drinking water containing 1% taurine. We evaluated blood pressure, renal function, renal LOX-1 expression and parameters for oxidative stress. In salt-loaded DS rats, there was a significant increase in heart weight and urinary protein, accompanied with enhanced LOX-1 expression in kidney. All of these were reduced by concomitant supplementation of taurine, although both antihypertensive and antihyperlipidemic effects of taurine were only slight in salt-loaded DS rats. On the other hand, salt-induced increment in urinary 8-hydroxy-deoxyguanosine, a parameter of oxidative damage, was completely normalized by taurine supplementation. The protective effects of taurine supplementation against renal damage induced by salt loading in DS rats may be attributed to the suppression of LOX-1, probably through its antioxidant effects.