B‐Type natriuretic peptide suppression of neutrophil superoxide generation: mechanistic studies in normal subjects

Many acute cardiovascular disease states are associated with neutrophil infiltration of myocardium and subsequent release of superoxide (O₂^?) and myeloperoxidase (MPO), which contribute to inflammatory reactions. B‐Type natriuretic peptide (BNP) is known to exert anti‐inflammatory and antifibrotic effects, but it is not known whether these may include interactions with neutrophils. In neutrophils isolated from 20 healthy subjects, we assessed the effect of BNP on the ‘neutrophil burst’ (O₂^? production and MPO release) stimulated by phorbol myristate acetate (PMA) and N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP), respectively. Effects of BNP on cGMP accumulation, and the effects of the cell‐permeable cGMP analogue 8‐(4‐chlorophenylthio) guanosine‐cGMP (8‐p‐CPT‐cGMP) and protein kinase G (PKG) inhibition with KT5823 on the neutrophil–BNP interaction were also evaluated. B‐Type natriuretic peptide suppressed O₂^? release from neutrophils by 23 ± 6% (P < 0.001) and 24 ± 8% (P < 0.05) following PMA and fMLP stimulation, respectively. Although BNP did not significantly increase cGMP formation, 8‐p‐CPT‐cGMP suppressed both PMA‐ and fMLP‐induced neutrophil O₂^? release by 16% and 28%, respectively (P < 0.05). The PKG inhibitor KT5823 attenuated the effects of BNP on both fMLP‐ and PMA‐associated O₂^? production. Neither BNP nor 8‐p‐CPT‐cGMP significantly affected MPO release from neutrophils. Suppression of O₂^? release from neutrophils by BNP may contribute to its anti‐inflammatory and antifibrotic actions.     

Oral administration of alcalase potato protein hydrolysate‐APPH attenuates high fat diet‐induced cardiac complications via TGF‐β/GSN axis in aging rats

Consumption of high fat diet (HFD) is associated with increased cardiovascular risk factors among elderly people. Aging and obesity induced‐cardiac remodeling includes hypertrophy and fibrosis. Gelsolin (GSN) induces cardiac hypertrophy and TGF‐β, a key cytokine, which induces fibrosis. The relationship between TGF‐β and GSN in aging induced cardiac remodeling is still unknown. We evaluated the expressions of TGF‐β and GSN in HFD fed 22 months old aging SD rats, followed by the administration of either probucol or alcalase potato protein hydrolysate (APPH). Western blotting and Masson trichrome staining showed that APPH (45 and 75 mg/kg/day) and probucol (500 mg/kg/day) treatments significantly reduced the aging and HFD‐induced hypertrophy and fibrosis. Echocardiograph showed that the performance of the hearts was improved in APPH, and probucol treated HFD aging rats. Serum from all rats was collected and H9c2 cells were cultured with collected serums separately. The GSN dependent hypertrophy was inhibited with an exogenous TGF‐β in H9c2 cells cultured in HFD+ APPH treated serum. Thus, we propose that along with its role in cardiac fibrosis, TGF‐β also acts as an upstream activator of GSN dependent hypertrophy. Hence, TGF‐β in serum could be a promising therapeutic target for cardiac remodeling in aging and/or obese subjects.     

Effects of nitric oxide on large‐conductance Ca2+‐activated K+ currents in human cardiac fibroblasts through PKA and PKG‐related pathways

The human cardiac fibroblast (HCF) is the most abundant cell type in the myocardium, and HCFs play critical roles in maintaining normal cardiac function. However, unlike cardiomyocytes, the electrophysiology of HCFs is not well established. In the cardiovascular system, Ca²⁺‐activated K⁺ (KCa) channels have distinct physiological and pathological functions, and nitric oxide (NO) plays a key role. In this study, we investigated the potential effects of NO on KCa channels in HCFs. We recorded strong oscillating, well‐maintained outward K⁺ currents without marked inactivation throughout the test pulse period and detected outward rectification in the I‐V curve; these are all characteristics that are typical of KCa currents. These currents were blocked with iberiotoxin (IBTX, a BKCa blocker) but not with TRAM‐34 (an IKCa blocker). The amplitudes of the currents were increased with SNAP (an NO donor), and these increases were inhibited with IBTX. The SNAP‐stimulating effect on the BKCa currents was blocked by pretreatment with KT5823 (a protein kinase G [PKG] inhibitor) or 1 H‐[1,‐2, ‐4] oxadiazolo‐[4,‐3‐a] quinoxalin‐1‐one (ODQ; a soluble guanylate cyclase inhibitor). Additionally, 8‐bromo‐cyclic guanosine 3’,5’‐monophosphate (8‐Br‐cGMP) stimulated the BKCa currents, and pretreatment with KT5720 (a protein kinase A [PKA] inhibitor) and SQ22536 (an adenylyl cyclase inhibitor) blocked the NO‐stimulating effect on the BKCa currents. Furthermore, 8‐bromo‐cyclic adenosine 3’,5’‐monophosphate (8‐Br‐cAMP) activated the BKCa currents. These data suggest that BKCa current is the main subtype of the KCa current in HCFs and that NO enhances these currents through the PKG and PKA pathways.     

Telmisartan attenuates peritoneal fibrosis via peroxisome proliferator‐activated receptor‐γ activation in rats

Peritoneal dialysis (PD) is an effective treatment for patients with end‐stage renal diseases, but long‐term continuous PD causes peritoneal fibrosis (PF). This study aims to evaluate the anti‐fibrotic effect of telmisartan on a rat model of PF and to investigate the underlying mechanisms. Five‐sixths kidney nephrectomy and PD were used to establish the PF rat model. Glucose (2.5%) was used to establish an in vitro model in rat peritoneal mesothelial cells (PMC). Haematoxylin–eosin staining was used to examine the structural alterations. Masson's trichrome staining was used to observe the tissue fibrosis in peritoneal membrane of rats. Real‐time polymerase chain reaction was used to measure messenger RNA expressions of profibrotic factors. Western blotting was used to determine protein expressions of profibrotic factors, peroxisome proliferator‐activated receptor‐γ, and mitogen‐activated protein kinases (MAPK). Results demonstrated that administration of telmisartan dose‐dependently attenuated the thickening of the peritoneal membrane and the fibrosis induced by long‐term PD fluid exposure in rats. In addition, telmisartan treatment inhibited the upregulation of profibrotic factors induced by PD in the peritoneum of rats and by high‐concentration glucose in PMC. Telmisartan was also effective in inhibiting PD and high‐concentration, glucose‐induced phosphorylation of MAPK in the peritoneum and PMC. Furthermore, peroxisome proliferator‐activated receptor‐γ (PPARγ) inhibitor GW9662 blocked these protective effects of telmisartan in PMC. The results suggest that telmisartan is effective in attenuating PD‐induced PF, and this effect may be associated with the inhibition of profibrotic factor expression and MAPK phosphorylation via PPARγ activation.     

Upregulation of C/EBPβ and TSC2 by an HDAC inhibitor CG200745 protects heart from DOCA‐induced hypertrophy

Histone deacetylases (HDACs) are a vast family divided into four major classes: class I (1, 2, 3, and 8), class II (4, 5, 6, 7, 9 and 10), class III (sirtuin family) and class IV (HDAC11). HDAC inhibition attenuates cardiac hypertrophy through suppression of the mechanistic target of rapamycin complex1 (mTORC1) signaling. HDAC inhibitors upregulate the expression of tuberous sclerosis complex 2 (TSC2), an mTORC1 inhibitor. However, the molecular mechanism underlying HDAC inhibitor‐mediated upregulation of TSC2 is unclear. We hypothesized that an HDAC inhibitor, CG200745 (CG), ameliorates cardiac hypertrophy through the inhibition of mTORC1 signaling by upregulating of the CCAAT/enhancer‐binding protein‐β (C/EBP‐β)/TSC2 pathway. To establish a cardiac hypertrophy model, deoxycorticosterone acetate (DOCA, 40 mg/kg/wk) was subcutaneously injected for 4 weeks into Sprague‐Dawley rats. All rats were unilaterally nephrectomized and had free access to drinking water containing 1% NaCl with or without CG of different concentrations. The expression level of TSC2 and C/EBP‐β was measured by quantitative real‐time PCR (qRT‐PCR) and western blot analysis. Acetylation of C/EBP‐β was analyzed by immunoprecipitation. The recruitment of C/EBP‐β and polymerase II (Pol II) on TSC2 promoter region was analyzed by chromatin immunoprecipitation (ChIP). CG treatment increased the expression of TSC2. In addition, CG treated rats showed an increased in the expression and acetylation of C/EBP‐β, owing to the increase in the recruitment of C/EBP‐β and Pol II at Tsc2 gene promoter. Thus, CG ameliorates cardiac hypertrophy through the inhibition of mTORC1 signaling via upregulation of the C/EBP‐β/TSC2 pathway in DOCA‐induced hypertensive rats.     

Icariin attenuates high glucose‐induced type IV collagen and fibronectin accumulation in glomerular mesangial cells by inhibiting transforming growth factor‐β production and signalling through G protein‐coupled oestrogen receptor 1

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Metformin attenuates ventricular hypertrophy by activating the AMP-activated protein kinase-endothelial nitric oxide synthase pathway in rats

1. Metformin is an activator of AMP‐activated protein kinase (AMPK). Recent studies suggest that pharmacological activation of AMPK inhibits cardiac hypertrophy. In the present study, we examined whether long‐term treatment with metformin could attenuate ventricular hypertrophy in a rat model. The potential involvement of nitric oxide (NO) in the effects of metformin was also investigated. 2. Ventricular hypertrophy was established in rats by transaortic constriction (TAC). Starting 1 week after the TAC procedure, rats were treated with metformin (300 mg/kg per day, p.o.), N^G‐nitro‐l‐ arginine methyl ester (l ‐NAME; 50 mg/kg per day, p.o.) or both for 8 weeks prior to the assessment of haemodynamic function and cardiac hypertrophy. 3. Cultured cardiomyocytes were used to examine the effects of metformin on the AMPK–endothelial NO synthase (eNOS) pathway. Cells were exposed to angiotensin (Ang) II (10^?6 mol/L) for 24 h under serum‐free conditions in the presence or absence of metformin (10^?3 mol/L), compound C (10^?6 mol/L), l ‐NAME (10^?6 mol/L) or their combination. The rate of incorporation of [³H]‐leucine was determined, western blotting analyses of AMPK–eNOS, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) were undertaken and the concentration of NO in culture media was determined. 4. Transaortic constriction resulted in significant haemodynamic dysfunction and ventricular hypertrophy. Myocardial fibrosis was also evident. Treatment with metformin improved haemodynamic function and significantly attenuated ventricular hypertrophy. Most of the effects of metformin were abolished by concomitant l ‐NAME treatment. l ‐NAME on its own had no effect on haemodynamic function and ventricular hypertrophy in TAC rats. 5. In cardiomyocytes, metformin inhibited AngII‐induced protein synthesis, an effect that was suppressed by the AMPK inhibitor compound C or the eNOS inhibitor l ‐NAME. The improvement in cardiac structure and function following metformin treatment was associated with enhanced phosphorylation of AMPK and eNOS and increased NO production. 6. The findings of the present study indicate that long‐term treatment with metformin could attenuate ventricular hypertrophy induced by pressure overload via activation of AMPK and a downstream signalling pathway involving eNOS–NO.     

Thiazolidinediones improve hepatic fibrosis in rats with non‐alcoholic steatohepatitis by activating the adenosine monophosphate‐activated protein kinase signalling pathway

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Specific α7 nicotinic acetylcholine receptor agonist ameliorates isoproterenol‐induced cardiac remodelling in mice through TGF‐β1/Smad3 pathway

It is well‐accepted that inflammation plays an important role in the development of cardiac remodelling and that therapeutic approaches targeting inflammation can inhibit cardiac remodelling. Although a large amount of evidence indicates that activation of α7 nicotinic acetylcholine receptor (α7nAChR) causes an anti‐inflammatory effect, the role of α7nAChR in cardiac remodelling and the underlying mechanism have not been established. To investigate the effect of the specific α7nAChR agonist, PNU282987, on cardiac remodelling induced by isoproterenol (ISO 60 mg/kg per day) in mice, the cardiomyocyte cross‐sectional area (CSA) and collagen volume fraction were evaluated by hematoxylin and eosin (HE) and Masson staining, respectively. Cardiac function and ventricular wall thickness were measured by echocardiography. The protein expressions of collagen I, matrix metalloproteinase 9 (MMP‐9), transforming growth factor β1 (TGF‐β1), and Smad3 were analyzed by Western blot. ISO‐induced cardiac hypertrophy, characterized by an increase in the heart weight/body weight ratio, CSA and ventricular wall thickness. Moreover, cardiac fibrosis indices, such as collagen volume fraction, MMP‐9 and collagen I protein expression, were also increased by ISO. PNU282987 not only attenuated cardiac hypertrophy but also decreased the cardiac fibrosis induced by ISO. Furthermore, PNU282987 suppressed TGF‐β1 protein expression and the phosphorylation of Smad3 induced by ISO. In conclusion, PNU282987 ameliorated the cardiac remodelling induced by ISO, which may be related to the TGF‐β1/Smad3 pathway. These data imply that the α7nAChR may represent a novel therapeutic target for cardiac remodelling in many cardiovascular diseases.     

Adipose‐derived mesenchymal stem cells therapy for acute kidney injury induced by ischemia‐reperfusion in a rat model

Acute kidney injury (AKI) represents a group of complicated syndromes with a high mortality rate. The administration of adipose‐derived mesenchymal stem cells (ADMSCs) has been tested as a possible treatment method for AKI. The long‐term evaluation of AKI induced by ischemia/reperfusion (IR) and the probable renal protection of ADMSCs are limited. In this study we have established a rat AKI model induced by IR and investigated the possible protective effects of ADMSCs. Adult Sprague‐Dawley (SD) rats were divided into three groups (n = 6/each group). The MOCK group was as the normal control. Rats in the IR‐AKI and IR‐AKI+ADMSCs groups were subjected to IR injury by clamping both renal pedicles for 40 minutes. Rats in the MOCK and IR‐AKI groups were injected with PBS via the tail vein as negative treatment controls. Rats in the IR‐AKI+ADMSCs group received ADMSCs therapy (2 × 10⁶ cells were injected into the rats via the tail vein). We found that ADMSC transplantation restored the pathologic morphology induced by IR‐AKI to normal compared with the MOCK group, suggesting the reparative function of ADMSCs in kidney tissues. Compared with IR‐induced AKI alone, ADMSC treatment significantly decreased the number of apoptotic cells, the level of total urinary protein and serum creatinine, the expression of pro‐inflammatory cytokines (IL‐6, TNF‐α, IL‐1β, IFN‐γ, TNF‐α, IFN‐γ, and TGF‐β), and the inflammation‐associated proteins (HGF and SDF1), but increased the expression of the anti‐inflammatory cytokine, IL‐10, and the anti‐apoptotic regulator, Bcl‐2. Our data have indicated that ADMSC transplantation may protect against IR‐induced AKI by anti‐apoptotic and anti‐inflammatory effects.     

Heat‐killed Salmonella typhimurium mitigated radiation‐induced lung injury

Radiation‐induced lung injury (RILI) is a serious complication in thoracic tumour radiotherapy. It often occurs in clinical chest radiotherapy and acute whole‐body irradiation (WBI) caused by nuclear accidents or nuclear weapon attack. Some radioprotective agents have been reported to exert protective effects when given prior to radiation exposure, however, there is no treatment strategy available for preventing RILI. In this study, we demonstrated that heat‐killed Salmonella typhimurium (HKST), a co‐agonist of Toll‐like receptors 2 (TLR2), Toll‐like receptors 4 (TLR4) and Toll‐like receptors 5 (TLR5), mitigated radiation‐induced lung injury through the transforming growth factor‐β (TGF‐β) signalling pathway. We found that HKST alleviated lung hyperaemia and pathological damage after irradiation, indicated that HKST inhibits the early inflammatory reaction of radiation‐induced lung injury. Then, for the first time, we observed HKST reduced collagen deposit induced by irradiation in the later phase (7‐14 week) of RILI, and we found that HKST inhibited radiation‐induced cell apoptosis in lung tissues. We found that HKST reduced the level of TGF‐β and regulated its downstream signalling pathway. Finally, it was found that HKST inhibited radiation‐induced epithelial–mesenchymal transition (EMT) in lung tissues. In conclusion, our data showed that HKST effectively mitigated RILI through regulating TGF‐β, provide novel treatment strategy for RILI in whole‐body irradiation and radiotherapy.     

Oestrogen upregulates the sarcoplasmic reticulum Ca2+ ATPase pump in coronary arteries

The presence of circulating plasma 17β‐oestradiol (E2) is beneficial in women against abnormal vascular tone development, such as coronary arterial vasospasms. Several vascular diseases have demonstrated that increased expression of the sarcoplasmic reticulum Ca²⁺‐ATPase pump (SERCA2b) serves to limit the excessive accumulation of intracellular Ca²⁺. Therefore, the hypothesis of the present study was that E2 would increase SERCA2b expression in the coronary vasculature. Coronary arteries were dissected from hearts obtained from mature female pigs. Artery segments were cultured for 24 h in E2 (1 pmol/L or 1 nmol/L) and homogenized for western blot analysis. At 1 nmol/L, E2 induced an approximate 50% increase in immunoreactivity for SERCA2b. In addition, E2 increased the protein expression of the known SERCA regulatory proteins, protein kinase A (PKA) and protein kinase G (PKG). The E2‐induced increase in SERCA2b was attenuated when the culture medium was supplemented with the oestrogen receptor (ER) α/β antagonist ICI 182,780 and the PKG antagonist KT5823 (10 μmol/L, 24 h for both). The PKA antagonist (KT5720; 10 μmol/L, 24 h) had no effect on SERCA2b expression. Removal of the endothelium (using a wooden toothpick) from artery segments prior to culture decreased the E2‐mediated increase in SERCA2b and PKG expression by 45% and 47%, respectively. Overall, the findings suggest that one of the potential cardiovascular benefits of E2 in women is upregulation of SERCA2b, via activation of the classic ERα and ERβ pathway.     

Epigallocatechin gallate attenuates fibroblast proliferation and excessive collagen production by effectively intervening TGF‐β1 signalling

Pulmonary fibrosis (PF) poses a huge burden to the patients and society due to lack of an effective treatment drug. Activation of fibrocyte, fibroblast and myofibroblasts are important steps in the development of PF. Targeting this common pathway with natural chemicals may lead to the development of new drug regimens for PF treatment. In this study, PF was induced in male Wistar rats by intratracheal administration of Bleomycin (BLM). Epigallocatechin gallate (EGCG) was administered to one of the groups of rats to test its efficacy against the development of PF. Bleomycin‐induction resulted in significant elevation of matrix metalloproteinase (MMP)‐2 and ‐9 expression, increased RNA and protein expression of transforming growth factor (TGF)‐β1, Smads and alpha‐smooth muscle actin (α‐SMA). EGCG treatment normalized the BLM induced aberrations in these rats. The protective role of EGCG was also validated in vitro using the WI‐38 fibroblast cell line. TGF‐β1 incubated cells exhibited increased fibroblast proliferation and hydroxyproline levels with a concomitant decrease in the expression of MMPs 2 and 9. An increase in protein expression levels of p‐Smad, α‐SMA and type I collagen (COL1A) was also exhibited by fibroblasts upon TGF‐β1 incubation. Simultaneous treatment of EGCG to WI‐38 cells significantly decreased these protein expressions alongside normalizing the MMPs expression. The study revealed that EGCG inhibited fibroblast activation and collagen accumulation by inhibiting TGF‐β1 signalling and thus can be considered as an effective drug against PF.     

Hyperlipidaemia induced by a high-cholesterol diet leads to the deterioration of guanosine-3′,5′-cyclic monophosphate/protein kinase G-dependent cardioprotection in rats

Background and purpose:

Hyperlipidaemia interferes with cardioprotective mechanisms, but the cause of this phenomenon is largely unknown, although hyperlipidaemia impairs the cardioprotective NO–cGMP system. However, it is not known if natriuretic peptide–cGMP–protein kinase G (PKG) signalling is affected by hyperlipidaemia. Therefore, we investigated the cardioprotective efficacy of cGMP-elevating agents in hearts from normal and hyperlipidaemic rats.

Experimental approach:

Male Wistar rats were rendered hyperlipidaemic by feeding with 2% cholesterol-enriched chow for 12 weeks. Hearts isolated from normal and hyperlipidaemic rats were perfused (Langendorff mode) and subjected to 30 min occlusion of the left main coronary artery, followed by 120 min reperfusion. 8-Br-cGMP (CG, 10 nM), B-type natriuretic peptide-32 (BNP, 10 nM), S-nitroso-N-acetyl-penicillamine (SNAP, 1 µM) were perfused from 10 min prior to coronary occlusion until the 15th min of reperfusion. Infarct size (% of ischaemic risk zone) was determined by triphenyltetrazolium staining.

Key results:

Treatment with CG, SNAP or BNP decreased infarct size significantly in normal hearts from its control value of 41.6 ± 2.9% to 15.5 ± 2.4%, 23.3 ± 3.0% and 25.3 ± 4.6%, respectively (P < 0.05). Protection by BNP was abolished by co-perfusion of PKG inhibitors KT5823 (600 nM) or Rp-8pCPT-PET-cGMPs (1 µM), confirming its PKG dependence. In hearts from hyperlipidaemic rats, CG, SNAP or BNP failed to decrease infarct size. Hyperlipidaemia did not alter basal myocardial PKG content, but decreased its activity as assessed by phosphorylation of cardiac troponin I.

Conclusions and implications:

This is the first demonstration that defects in the cardioprotective cGMP–PKG system could be a critical biochemical anomaly in hyperlipidaemia.     

A distinct AMP‐activated protein kinase phosphorylation site characterizes cardiac hypertrophy induced by l‐thyroxine and angiotensin II

1. The purpose of the present study was to evaluate differences in the AMP‐activated protein kinase (AMPK) phosphorylation sites in cardiac hypertrophy induced by l ‐thyroxine and angiotensin (Ang) II. 2. Cardiac hypertrophy was induced in wild‐type and AMPKα2‐knockout mice by treatment with 1 mg/kg, i.p., thyroxine or 1.44 mg/kg per day AngII for 14 days. The phenotype of the hypertrophy was evaluated using echocardiographic measurments and histological analyses. The phosphorylation of AMPK at α‐Ser^485/491 and α‐Thr¹⁷² was determined by western blot analysis. 3. In wild‐type mice, the phosphorylation of AMPKα‐Ser^485/491 was significantly elevated in the AngII‐treated group, but not in the thyroxine‐reated group, compared with the vehicle control group. In contrast, the phosphorylation of AMPKα‐Thr¹⁷² was significantly increased by thyroxine, but not AngII, treatment compared with the vehicle control group. Furthermore, knockout of the AMPKα2 subunit abolished phosphorylation at the α‐Ser^485/491 site and significantly suppressed phosphorylation at the α‐Thr¹⁷² site, resulting in alleviation of thyroxine‐ but not AngII‐induced hypertrophy. 4. In conclusion, l ‐thyroxine and AngII induce the phosphorylation of distinct sites of AMPK in cardiac hypertrophy. Phosphorylation of AMPK α‐Thr¹⁷² may contribute to thyroxine‐induced cardiac hypertrophy.     

Antifibrotic effects of D‐limonene (5(1‐methyl‐4‐[1‐methylethenyl]) cyclohexane) in CCl4 induced liver toxicity in Wistar rats

This study was designed to assess the potential antifibrotic effect of D‐Limonene—a component of volatile oils extracted from citrus plants. D‐limonene is reported to have numerous therapeutic properties. CCl₄‐intduced model of liver fibrosis in Wistar rats is most widely used model to study chemopreventive studies. CCl₄‐intoxication significantly increased serum aminotransferases and total cholesterol these effects were prevented by cotreatment with D‐Limonene. Also, CCl₄‐intoxication caused depletion of glutathione and other antioxidant enzymes while D‐Limonene preserved them within normal values. Hydroxyproline and malondialdehyde content was increased markedly by CCl₄ treatment while D‐Limonene prevented these alterations. Levels of TNF‐α, TGF‐β, and α‐SMA were also assessed; CCl₄ increased the expression of α‐SMA, NF‐κB and other downstream inflammatory cascade while D‐Limonene co‐treatment inhibited them. Collectively these findings indicate that D‐Limonene possesses potent antifibrotic effect which may be attributed to its antioxidant and anti‐inflammatory properties.     

Long‐Term Physical Exercise and Atrial Natriuretic Peptide in Obese Zucker Rats

Abstract: Endurance training increases natriuretic peptide synthesis in the hypertrophied myocardium of spontaneously hypertensive rats. We examined the effects of 22‐week‐long treadmill exercise on plasma and tissue atrial natriuretic peptide in Zucker rats, a model of genetic obesity and moderate hypertension without clear cardiac hypertrophy. The blood pressures of the animals were measured by the tail‐cuff method, and plasma and tissue samples for the peptide determinations were taken at the end of the study. The training increased heart weight to body weight ratio, while atrial natriuretic peptide contents in the right and left atrium, ventricular tissue, and plasma did not change. The exercise prevented the elevation of blood pressure, which was observed in non‐exercised obese Zucker rats, and also reduced blood pressure in the lean rats. In conclusion, these results suggest that in the absence of preceding myocardial hypertrophy, the long‐term exercise‐induced workload is not deleterious to the heart in experimental obesity, since no changes in plasma and tissue atrial natriuretic peptide were detected.     

Deep sea minerals prolong life span of streptozotocin‐induced diabetic rats by compensatory augmentation of the IGF‐I‐survival signaling and inhibition of apoptosis

Consumption of deep sea minerals (DSM), such as magnesium, calcium, and potassium, is known to reduce hypercholesterolemia‐induced myocardial hypertrophy and cardiac‐apoptosis and provide protection against cardiovascular diseases. Heart diseases develop as a lethal complication among diabetic patients usually due to hyperglycemia‐induced cardiac‐apoptosis that causes severe cardiac‐damages, heart failure, and reduced life expectancy. In this study, we investigated the potential of DSM and its related cardio‐protection to increase the life expectancy in diabetic rats. In this study, a heart failure rat model was developed by using streptozotocin (65 mg kg^?1) IP injection. Different doses of DSM‐1× (37 mg kg^?1 day^?1), 2× (74 mg kg^?1 day^?1) and 3× (111 mg kg^?1 day^?1), were administered to the rats through gavages for 4 weeks. The positive effects of DSM on the survival rate of diabetes rats were determined with respect to the corresponding effects of MgSO₄. Further, to understand the mechanism by which DSM enhances the survival of diabetic rats, their potential to regulate cardiac‐apoptosis and control cardiac‐dysfunction were examined. Echocardiogram, tissue staining, TUNEL assay, and Western blotting assay were used to investigate modulations in the myocardial contractile function and related signaling protein expression. The results showed that DSM regulate apoptosis and complement the cardiomyocyte proliferation by enhancing survival mechanisms. Moreover DSM significantly reduced the mortality rate and enhanced the survival rate of diabetic rats. Experimental results show that DSM administration can be an effective strategy to improve the life expectancy of diabetic subjects by improving cardiac‐cell proliferation and by controlling cardiac‐apoptosis and associated cardiac‐dysfunction. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 769–781, 2016.