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AIM: To analyze the role and mechanism of PDGF/AKT pathway in pressure overload-induced ventricular remodeling. METHODS: A total of 55 C57BL/6 female mice were selected to establish aortic arch narrowing model. Forty-five models were successfully modeled. The randomized digital table method was used to divide the models into sham operation group, DMSO group and experimental group. The sham operation group was opened after chest operation. The suture was performed without aortic coarctation (TAC). After 24 hours of thoracotomy, 200 μL of PBS solution and 50 μL of DMSO were administered. The DMSO group was given 200 μL of PBS solution and 50 μL of DMSO 24 h after operation. The experimental group was given PBS solution 200 μL plus AG1296 50 μL 24 h after TAC to observe the heart function and myocardial histopathology of mice. Lentiviral infection was established to identify and culture HUVEC cells with different expression of PDGF gene. According to different treatments, the cells were divided into control group, PDGF group, shRNA group and PDGF+IMA group to detect the expression of p-AKT and t-AKT protein in HUVEC cells. RESULTS:LVESV, LVEDV, LVESD and LVEDD were increased in DMSO group as compared with sham operation group, while EF and FS of DMSO group were lower than those in sham operation group. LVESV, LVEDV, LVESD and LVEDD were lower in experimental group than those in DMSO group, while EF and FS in experimental group were higher than those in DMSO group. The difference was statistically significant (P<0.05). The sham operation group had neatly arranged myocardial tissue and normal interstitial; the DMSO group had irregular morphology, inflammatory cell infiltration, cell gap was enlarged, and the nucleus was deeply stained. The number of expanded or necrotic cells in experimental group decreased, the gap became smaller, and the inflammatory infiltration decreased. The cross-sectional area of myocardial cells in DMSO group was higher than that in sham operation group. The cross-sectional area of the myocardial cells in experimental group was lower than that in DMSO group (P<0.05). The expression of p-AKT and t-AKT protein in PDGF+IMA group was significantly higher than that in PDGF group and shRNA group, the difference was statistically significant (P<0.05). CONCLUSION:PDGF can accelerate ventricular remodeling induced by pressure overload and promote the formation of myocardial fibrosis, while inhibiting PDGF/AKT pathway can improve myocardial cell hypertrophy.
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This study aimed to explore the role of miR-130a-3p in cardiomyocyte hypertrophy and its underlying mechanisms. Pressure-overload induced myocardial hypertrophy mice model was constructed by thoracic aortic constriction (TAC). , norepinephrine (NE) was used to stimulate neonatal rat cardiomyocytes (NRCMs) and H9c2 rat cardiomyocytes to induce hypertrophic phenotypes. The expression of miR-130a-3p was detected in mice hypertrophic myocardium, hypertrophic NRCMs and H9c2 cells. The mimics and inhibitors of miR-130a-3p were transfected into H9c2 cells to observe the role of miR-130a-3p on the hypertrophic phenotype change of cardiomyocytes separately. Furthermore, whether miR-130a-3p regulated hypertrophic related signaling pathways was explored. The results showed that the expression of miR-130a-3p was significantly decreased in hypertrophic myocardium, hypertrophic NRCMs and H9c2 cells. After transfection of miR-130a-3p mimics, the expression of hypertrophic marker genes, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC), and the cell surface area were notably down-regulated compared with the control group (mimics N.C. + NE group). But after transfection of miR-130a-3p inhibitor, the expression of ANP, BNP and β-MHC in H9c2 cells increased significantly, and the cell area increased further. By Western blot, it was found that the protein phosphorylation level of Akt and mTOR were down-regulated after over-expression of miR-130a-3p. These results suggest that miR-130a-3p mimics may alleviate the degree of cardiomyocyte hypertrophy, meanwhile its inhibitor can further aggravate cardiomyocyte hypertrophy. Over-expression of miR-130a-3p may attenuate cardiomyocytes hypertrophy by affecting the Akt pathway.
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Animals , Mice , Rats , Atrial Natriuretic Factor , Cardiomegaly , MicroRNAs , Genetics , Myocardium , Pathology , Myocytes, Cardiac , Pathology , Myosin Heavy Chains , Natriuretic Peptide, Brain , Nonmuscle Myosin Type IIB , Proto-Oncogene Proteins c-aktABSTRACT
Aim To investigate the inhibitory effect of cistanche phenylethanol glycosides (CPhGs) on cardiac hypertrophy in rats caused by pressure overload and its related mechanism. Methods Male SD rats(n =70) were randomly divided into control group (Con), sham operation group (Sham), model group (Mod), positive control group (Vst), and different CPhGs dosage (125, 250, 500 mg • kg-1) groups. Cardiac ultrasound indexes, heart-weight to body-weight index (HWI), cardiac histopathological changes, and the area of myocardical cells (AMC) were detected. Plasma ET-1 and BNP levels were detected by Elisa, and protein expressions of phosphorylated PI3K(p-PI3K), PI3K, phosphorylated PKB (p-pKB) and PKB were detected by Western blot. Results Compared with Mod group, LVPWT, HWI, plasma ET-1, BNP and AMC decreased to different degrees. LVEDD, LVEF, LVFS, the protein expressions of myocardial tissues pPI3K and p-PKB increased to different degrees in CPhGs groups. Moreover, the indexes of CPhGs 250 and 500 mg • kg-1 groups were significantly improved compared to those of Mod group (P < 0. 05 or 0. 01). Compared with Vst group, there were no significant difference in CPhGs 500 mg • kg-1 group. Conclusions CPhGs could inhibit cardiac hypertrophy in rats induced by pressure overload, which might be related to the activation of PI3K/PKB signaling pathway.
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AIM:To investigate the protective effect of zacopride (ZAC) on the pressure-overload left ventricular remodeling in the rats induced by coarctation of abdominal aorta.METHODS:Male Sprague-Dawley (SD) rats with pressure overload were induced by the coarctation of abdominal aorta.The model rats were intraperitoneally administered with ZAC, chloroquine (Chlor) , and zacopride+chlorquine (ZAC+Chlor).The study duration was 8 weeks.The cardiac structure and function were assessed by echocardiography.The heart weight/body weight (HW/BW) ratio and the left ventricular weight/body weight (LVW/BW) ratio were calculated.The changes of structure and shape in myocardial tissue were observed with HE staining.The ultrastructure of the myocytes was observed under transmission electron microscope.The inward rectifier potassium channel (IK1) protein expression was determined by Western blot.The mRNA expression of Kir2.1 was detected by RT-PCR.RESULTS:Compared with vehicle group, ZAC improved cardiac function, as indicated by the decreased left ventricular end-diastolic dimension (LVEDD) and left ventricular end systolic dimension (LVESD) (P<0.05) , and the increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) (P<0.01).The HW/BW and LVW/BW ratios were significantly decreased, and the cross-sectional area of the cardiomyocytes was significantly less in ZAC group than that in vehicle group (P<0.01).The ultrastructure of the myocytes was significantly improved.Chlor blocked the protective effect of zacopride on the pressure-overload left ventricular remodeling.The protein level ofmRNA expression of Kir2.1 in the cardiac tissues in ZAC group were significantly increased compared with vehicle group (P<0.01).CONCLUSION:ZAC significantly attenuates pressure overload-induced ventricular remodeling in rats.
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AIM: To observe the dynamic changes of myocardial collagen metabolism in pressure-overloaded rats.METHODS: The pressure-overloaded rat model was established by partial abdominal aortic coarctation.The rats underwent surgery but not constrictive were used as sham-operated control group.The rats were euthanized at 3, 4, 8 and 12 weeks.The body mass, heart mass and left ventricular mass were weighed, and the heart mass index (HMI) and left ventricle mass index (LVMI) were calculated.Masson trichrome staining was used on the myocardial sections, alkaline hydrolysis was used to detect the content of myocardial hydroxyproline (HYP), and the serum levels of procollagen type I carboxy-terminal peptide (PICP), procollagen type III amino-terminal peptide (PIIINT), and collagen C telopeptide type I (CTX-I) were also measured.RESULTS: Compared with sham-operated control group, the collagen deposition was evident, and collagen volume fraction (CVF) was increased significantly in model group (P<0.01), which further increased over time.HMI, LVMI and HYP significantly increased in model group (P<0.05), and HYP showed a tendency to increase over time.In addition, the serum concentration of PICP was increased significantly in model group, and the difference was significant at 4, 8 and 12 weeks (P<0.05).The serum concentration of PIIINP was increased significantly, but CTX-I was lowered significantly in model group (P<0.01).CONCLUSION: In the state of pressure overload, myocardial collagen metabolism is in disorder, and myocardial fibrosis is the major pathological change, which further increases over time.
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Objective To observe whether the changes of electrocardiogram (ECG) is earlier than the morphological changes of ultrasonic cardiogram (UCG) during the development of cardiac pressure over-load left ventricular hypertrophy (LVH) in rabbits, so as to discuss the value of ECG in the early diagnosis of hypertensive LVH. Methods Forty male Japanese rabbits were randomly divided into experimental group (n=25) and control group (n=15). Rabbits in the experimental group were used to establish cardiac pressure over-load LVH model by subtotal ligation of suprarenal abdominal aorta. The control group received the same treatment as that in the experimental group except for the coarctation of abdominal aorta. Before operation and the 2nd, 4th, 6th, and 8th week after operation, 12-lead ECG were recorded to measure R-wave and QRS complex wave amplitude, heart electric axis, QRS duration and QTc period; UCG was performed to detect the thickness of left ventricular inferior wall (LVIW), posterior wall (LVPW) and interventricular septum (IVS), left ventricular end diastolic diameter (LVDd), left ventricular end systolic diameter (LVDs), E/A ratio and left ventricular ejection fraction (LVEF). Before operation and the 8th week after operation, chest X-ray examination was performed to detect cardiothoracic ratio. Then all the rabbits were sacrificed. Left ventricular mass indices (LVMI) were measured and cardiac pathological examination was performed. Results The blood pressure of rabbits increased gradually after operation in the experimental group, the cardiothoracic ratio and LVMI aggrandized, and the cardiomyocytes hypertrophy, denaturalization or necrosis were observed under microscope in the experimental group. The thickness of LVIW, LVPW and IVS of rabbits in the experimental group increased gradually, and the E/A ratio decreased gradually, showing significant difference when compared to those of the control group at the 4th week (P0.05). Conclusion During the development of cardiac pressure over-load LVH of rabbits, the electrical changes of ECG are earlier than the morphologic changes of UCG, which indicates that ECG may has a value for early diagnosis of the hypertensive LVH.
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Aim To study the influence of rosuvastatin on toll-like receptor 4 ( TLR4 ) , and its downstream nu-clear transcription factor NF-kappa B p65, IκBα, in-flammation factors TNF alpha in rats with myocardial hypertrophy induced by pressure overload .Methods Myocardial hypertrophy was induced by abdominal aor-tic constriction ( AAC ) .Male Wistar rats were divided into 3 groups(n=10):① sham-operated rats(S);②AAC rats(M);③AAC+rosuvastatin(10 mg· kg -1· d-1 ) rats.From 1 week pre-opertion to 4 weeks post-operation, three groups were performed by gavage ad-ministration with equal volume of rosuvastatin and vehi-cle.The rats underwent cardiac color Doppler exami-nation.The level of ANP,TLR4, NF-κB p65,IκBα, TNF-αmRNA and protein expression in myocardium were detected by real-time PCR, Western blot, immu-nohistochemical and ELISA respectively .Results The sizes of heart and cardiomyocytes and the expression of ANP mRNA and TLR4 signaling molecules were signif-icantly increased in group M , which could be blocked by rosuvastatin .TLR4 protein was positively related to ANP, NF-κB p65 and TNF-αrespectively .Conclusion Rosuvastatin prevents cardiac hypertrophy induced by pressure overload , which is associated with its inhi-bition of TLR4, NF-κB and TNF-αin myocardium ex-pression .
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Objective To analyze the electrocardiography ( ECG ) data of pressure overload ?induced chronic heart failure rats. Methods Totally 20 SD rats were randomly divided into sham operation group and heart failure group. Heart failure rats were induced by abdominal aorta constriction. Echocardiogram measurement demonstrated the occurrence of cardiac function. Two lead ECG parameters of limb a was measured and statistically analyzed. Results Ten weeks after operation, there was a increase in heart rate, P amplitude, P duration and R amplitude comparing by those of the sham operation group (P < 0?05). ECG showed a significant and ubiquitous J point elevation (P < 0?05), with ST segment notable depression ( P < 0?05 ) . Conclusions ECG in pressure?overload chronicity heart failure rats exhibits obviously characteristic features. ECG is an useful tool for objective and accurate assessment of cardiac function in rats.
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Objective To explore the effect of liraglutide on pressure?overload chronic heart failure in rats and related mechanisms. Methods Totally 30 SD rats were randomly divided into sham operation group, heart failure group and liraglutide group. The animals were anaesthetized and a Millar pressure volume conductance catheter SPR?838 ) was inserted through right carotid artery into LV to measure pressure?volume ( P?V ) loop. Body and organ weight were measured. After the end of intervention, the rats were anesthetized, and abdominal aortic blood taken from the upper serum after centrifugation. Kit method was used to measure superoxide dismutase (SOD), brain natriuretic peptide (BNP), malondialdehyde ( MDA) . Results Compared with those of the sham operation group, there was a increase in absolute heart weight and (P < 0?05). During the P?V loop analyses, We found that left ventricular (LV) end?systolic volume, end?diastolic volume, end?systolic pressure, end?diastolic pressure and maximum pressure were all remarkablely lower in liraglutide group than HF group in rats ( P < 0?05 ) . Peak rate of pressure rise ( dP/dt max ) , peak rate of pressure decline ( -dP/dt min) , ejection fraction and Maximum Power were increased in liraglutide group comparable by HF group (P < 0?05). SOD activity was significantly increased and BNP concentration was significantly decreased in liraglutide group compared to HF group (P < 0?05). Conclusions These results show that liraglutide protects pressure?overload rat heart from failure possibly through reducing oxidation.
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Objective Based on animal model of left ventricular pressure overload induced cardiac fibrosis,to investigate the specific role and molecular mechanism of KLF15 gene in this process.Methods To establish rat animal model of pressure overload induced cardiac hypertrophy by aortic coarctation under non artificial ventilation conditions,and then release the constriction,to observe the rat heart color Doppler images,myocardial interstitial fibrosis features and protein expression level changes of KLF15、Transforming growth factor-β (TGF-β) 、Connective tissue growth factor (CTGF)、Myocardin-related transcription factor A(MRTF-A) in overload-unload corresponding time points.Results We successfully completed aortic banding and debanding operations by use of SD rats without artificial ventilation.Through color Doppler echocardiography detection,from images to know:the effect of constriction and loosening is definite.The expression of collagen type Ⅰ,collagen type Ⅲ,TGF-β,CTGF,MRTF-A were significantly higher and myocardial hypertrophy was aggravated but the KLF15 protein expression level was significantly lower in pressure overloaded rats than in Sham rats(all P ＜ 0.05).All values were in an increasing tendency with the constrictive time prolonged (P ＜ 0.05).The response to unloading was opposite,the sooner to loose the better to the recovery to normal.The differences of indicators are very notable (P ＜ 0.05).Conclusion By feedback regulation TGF-β,KLF15 inhibited the effect of CTGF and MRTF-A,reducing myocardial interstitial fibrosis.
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Objective: To observe the protective roll of atorvastatin on post-operative cardiac remodeling induced by transverse aortic constriction (TAC) in experimental mice with its possible mechanism. Methods: A total of 48 C57BL/6 mice were randomly divided into 4 groups: Sham group, TAC group, TAC + valsartan group and TAC + atorvastatin group,n=12 in each group. Myocardial hypertrophy model was successfully established at 4 weeks after the operation, and then the animals were further treated by normal saline, valsartan 5mg/kg and atorvastatin 10mg/kg respectively for 8 weeks. Left ventricular anterior wall thickness at diastole (LVAWd), left ventricular posterior wall thickness at diastole (LVPWd), LVEF and left ventricular fractional shortening (FS) were examined by echocardiography, cardiac hypertrophy indexes were calculated. Protein expression of NF-κB was detected by Western blot analysis, cardiac tissue hydroxyproline (Hyp) level was measured by alkaline hydrolysis, serum levels of TNF-α, IL-1β were determined by ELISA, cardiac collagen deposition was identiifed by HE and Masson staining. Results: Compared with Sham group, TAC group had increased LVAWd, LVPWd, cardiac hypertrophy indexes and increased area of cardiac fibrosis, allP Conclusion: Atorvastatin had protective roll on myocardial hypertrophy induced by pressure overload in experimental mice, which might be related to its anti-inlfammatory effect.
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We examined the contractile responsiveness of rat thoracic aortas under pressure overload after long-term suprarenal abdominal aortic coarctation (lt-Srac). Endothelium-dependent angiotensin II (ANG II) type 2 receptor (AT2R)-mediated depression of contractions to ANG II has been reported in short-term (1 week) pressure-overloaded rat aortas. Contractility was evaluated in the aortic rings of rats subjected to lt-Srac or sham surgery (Sham) for 8 weeks. ANG I and II levels and AT2R protein expression in the aortas of lt-Srac and Sham rats were also evaluated. lt-Srac attenuated the contractions of ANG II and phenylephrine in the aortas in an endothelium-independent manner. However, lt-Srac did not influence the transient contractions induced in endothelium-denuded aortic rings by ANG II, phenylephrine, or caffeine in Ca2+-free medium or the subsequent tonic constrictions induced by the addition of Ca2+ in the absence of agonists. Thus, the contractions induced by Ca2+ release from intracellular stores and Ca2+ influx through stored-operated channels were not inhibited in the aortas of lt-Srac rats. Potassium-elicited contractions in endothelium-denuded aortic rings of lt-Srac rats remained unaltered compared with control tissues. Consequently, the contractile depression observed in aortic tissues of lt-Srac rats cannot be explained by direct inhibition of voltage-operated Ca2+ channels. Interestingly, 12-O-tetradecanoylphorbol-13-acetate-induced contractions in endothelium-denuded aortic rings of lt-Srac rats were depressed in the presence but not in the absence of extracellular Ca2+. Neither levels of angiotensins nor of AT2R were modified in the aortas after lt-Srac. The results suggest that, in rat thoracic aortas, lt-Srac selectively inhibited protein kinase C-mediated activation of contraction that is dependent on extracellular Ca2+ entry.
Subject(s)
Animals , Male , Aorta, Thoracic/physiopathology , Aortic Coarctation/physiopathology , Calcium/metabolism , Endothelium, Vascular/physiology , Muscle, Smooth, Vascular/physiopathology , Protein Kinase C/antagonists & inhibitors , Vasoconstriction/physiology , Angiotensin I/analysis , Angiotensin II/analysis , Aorta, Thoracic/injuries , Aorta, Thoracic/surgery , Blotting, Western , Blood Pressure/physiology , Chromatography, High Pressure Liquid , Endothelium, Vascular/injuries , Muscle, Smooth, Vascular/metabolism , Neuromuscular Depolarizing Agents/pharmacology , Phenylephrine/pharmacology , Potassium/pharmacology , Protein Kinase C/metabolism , Radioimmunoassay , Rats, Wistar , /metabolism , Vasoconstriction/drug effectsABSTRACT
Objective To study the effects of NRG2 on cardiac structure and function , we established the cardiac-specific human NRG2 transgenic mice and investigate the effect of NRG2 on cardiac structure and function under pressure overload situation .Methods The transgenic vector was constructed by insertion of the human NRG2 gene under the α-MHC promoter.The transgenic mice were generated by microinjection and were all maintained on a C57BL/6J genetic background .The genotype of transgenic mice was identified by PCR and the expression level of target gene was determined by western blot .Transverse aortic constriction ( TAC) was applied to prepare the pressure overload induced cardiomyopathy mice model .The cardiac structure and function of the transgenic mice were compared and analysized by echocardiographic and pathological observation .Results Transgenic mice with high level of NRG2 in heart tissues were established.The left ventricular wall thickness (LVPWD) was increased, and to 15.6% at 3 months old compared with that of the non transgenic ( NTG) mice.The hypertrophy of left ventricular wall caused by pressure overload was removed due to the expression of NRG2 .Meanwhile, cardiac disarray and fibrosis were increased obviously compared with that of the NTG mice.Conclusion The transgenic expression of NRG2 in heart tissues could shorten the pathological process of hypertrophy, but accelerated the process of heart failure (HF).
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AIM:To explore the effect of erythropoietin ( EPO) on the expression of myocardial NADPH oxi-dase (Nox) in the pressure overload rats.METHODS:Male SD rats (n=36) were used to establish a pressure overload myocardial hypertrophy model by abdominal aorta ligation.The animals were divided into model group, control group ( sham, without narrowing abdominal aorta, the rest of the operation was the same as the model) and recombinant human erythropoietin ( rhEPO) treatment group ( intraperitoneal injection of rhEPO postoperatively, 4 000 U/kg, twice a week) . After 8 weeks, the cardiac ultrasound imaging and hemodynamic evaluation were conducted to determine the cardiac func-tions.Masson staining was used to observe the degree of myocardial fibrosis.The expression of Nox2 and Nox4 at mRNA and protein levels was detected by real-time quantitative PCR and Western blotting.The protein levels of myocardial inflam-matory factors CD45, F4/80 and TGF-βwere determined by Western blotting.RESULTS:Compared with model group, the left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-systolic pressure (LVESP) and left ventricular pressure maximum rising and falling rates ( ±dp/dtmax) increased significantly in EPO treatment group (P<0.01).At the same time, left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter ( LVEDD) and left ventricular end-diastolic pressure ( LVEDP) were decreased in EPO treatment group (P<0.01).EPO reduced the degree of myocardial fibrosis caused by pressure overload (P<0.01) and decreased the ex-pression of Nox2 and Nox4 at mRNA and protein levels in the myocardium (P<0.05 or P<0.01), and reduced the pro-tein expression of myocardial inflammatory factors CD45, F4/80 and TGF-β.CONCLUSION: EPO inhibits rat myocar-dial fibrosis induced by pressure overload, improves heart functions by decreasing NADPH oxidase activity and inhibiting myocardial oxidative stress levels and myocardial inflammatory reaction.
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Objective: To explore the effect of exercise preconditioning (EP) on pathological cardiac hypertrophy and heart failure (HF) in pressure over-loaded experimental rats. Methods:A total of 60 SD rats at the age of 6 weeks were randomly divided into 3 groups, n=20 in each group. Sham-operation group, Transverse aortic constriction (TAC) group and EP + TAC group. The cardiac function and structure were evaluated by echocardiography, patholgical changes and HF biomarkers were examined for EP effect at 4 and 8 weeks after TAC. Results:Compared with Sham-operation group, the cardiac function and structure had obvious changes in the other 2 groups. Compared with TAC group, the ejection fraction in EP+ TAC group increased 15%, the heart weight index and left ventricular weight index decrease 15.7%and 20%respectively at 8 weeks after TAC, all P Conclusion: EP may improve cardiac pathological hypertrophy in pressure over-loaded rats at the early stage, and delay the heart failure process.
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AIM: To explore the changes in extracellular regulated protein kinase (ERK1/2) in the hypertrophic myocardium induced by pressure overload at the different time courses and to determine the molecular mechanism in the myocardium from hypertrophy to heart failure. METHODS: C57/BL mice, aged 12 week old, were subjected to sham-operation (SH) or transversing aortic constriction (TAC) to establish left ventricular hypertrophy. Echocardiographic assessments, hemodynamic determination, organ weight measurement, morphological and histological examination were performed at 1, 4, 8, 12 and 16 weeks after surgery. Meanwhile mRNA levels of atrial natriuretic peptide (ANP), α-myosin heavy chain (α-MHC), bcl-2 and bax were measured by RT-PCR, and ERK1/2 levels were detected by Western blotting. The animals in SH group were performed the same tests then sacrificed at 16 weeks. RESULTS: (1) Compared to SH group, LVESd, LVEDd, Awsth, Awdth, Pwsth and Pwdth progressively increased after TAC. Meanwhile, ejection fraction (EF%) significantly decreased at 16th week (P<0.05). LVSP, dp/dt_(max) and dp/dt_(min) in TAC group were progressively increased after 4 weeks. From 8-12 weeks these parameters maintained stable and then sharply decreased at 16th week (all P<0.05). However, LVEDP was statistically increased at 8th week. These echocardiographic and hemodynamic changes indicated a development of LVH and eventually progressing towards to heart failure. (2) Histologically, cardiac collagen measured by percentage of Sirius red positive stained area and apoptosis index showed progressive increases from 4 to 16 weeks. (3) Compared to SH group, mRNA levels of ANP was time-dependently increased while α-MHC and Bcl-2 were time-dependently decreased. The ratio of Bcl-2 /Bax was decreased. Phosphorylation of ERK1/2 was increased at 4th week, then decreased with age of TAC (all P<0.05). CONCLUSION: Pressure-overload induced by TAC results in a development of LVH from early concentric hypertrophy to late eccentric hypertrophy, and eventually toward cardiac dysfunction or heart failure. Those changes are associated with increase in cell size and cardiac fibrosis. ERK1/2 signaling pathway may involve in the regulation of myocardial cell apoptosis in hypertrophic and failure heart.
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Ventricular hypertrophy is one of the major myocardial responses to pressure overload (PO). Most studies on early myocardial response focus on the days or even weeks after induction of hypertrophic stimuli. Since mechanotransduction pathways are immediately activated in hearts undergoing increased work load, it is reasonable to infer that the myocardial gene program may be regulated in the first few hours. In the present study, we monitored the expression of some genes previously described in the context of myocardial hypertrophic growth by using the Northern blot technique, to estimate the mRNA content of selected genes in rat myocardium for the periods 1, 3, 6, 12 and 48 h after PO stimuli. Results revealed an immediate switch in the expression of genes encoding alpha and beta isoforms of myosin heavy chain, and up-regulation of the cardiac isoform of alpha actin. We also detected transitory gene regulation as the increase in mitochondrial cytochrome c oxidase 1 gene expression, parallel to down-regulation of genes encoding sarco(endo)plasmic reticulum Ca+2 ATPase and sodium-calcium exchanger. Taken together, these results indicate that initial myocardial responses to increased work load include alterations in the contractile properties of sarcomeres and transitory adjustment of mitochondrial bioenergetics and calcium availability.
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Pressure overload diseases such as valvular stenosis and systemic hypertension morphologically manifest in patients as cardiac concentric hypertrophy. Preventing cardiac remodeling due to increased pressure overload is important to reduce the morbidity and mortality. A recent clinical study has shown that carvedilol has beneficial effects on the survival rate of patients with heart failure. This may be due to the actions of carvedilol such as beta-adrenoceptor blockade and the alpha1-adrenergic receptor blockade effects. Therefore, we investigated whether carvedilol can reverse preexisting cardiac hypertrophy and we compared the effects of racemic carvedilol and the carvedilol enantiomers. Cardiac hypertrophy was induced in rats by suprarenal transverse abdominal aortic constriction (AC). Fifteen weeks after AC surgery, concentric hypertrophy was identified in the AC group by performing echocardiography. Low dose S- and SR-carvedilol (2 mg/kg/day), which were orally administered for three weeks, caused significant regression of the cardiac hypertrophy, and this most significantly occurred in the rats that received S-carvedilol. However, R-carvedilol did not reduce cardiac hypertrophy. Regression of cardiac hypertrophy by carvedilol was confirmed on the echocardiograms and electrocardiograms. These results suggest that carvedilol could reverse the development of leftventricular concentric hypertrophy that is induced by pressure overload. S-carvedilol is proposed to be superior to SR-and R-carvedilol as a beneficial treatment for cardiac hypertrophy.
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Animals , Humans , Rats , Carbazoles , Cardiomegaly , Constriction , Constriction, Pathologic , Echocardiography , Electrocardiography , Heart Failure , Hypertension , Hypertrophy , Propanolamines , Survival RateABSTRACT
OBJETIVO: Avaliar a contribuição relativa da remodelação geométrica do ventrículo esquerdo (VE) e das alterações morfológicas e funcionais do miocárdio, em ratos com estenose aórtica supravalvar (EAS), na fase de transição da hipertrofia compensada para a insuficiência cardíaca congestiva (ICC). MÉTODOS: Vinte e uma semanas após a indução da EAS os ratos foram classificados como controles (GC,n=13), não portadores (GE,n=11) ou portadores de insuficiência cardíaca congestiva (GE-IC,n=12).Todos os grupos foram avaliados com estudo ecocardiográfico, hemodinâmico e morfológico do miocárdio. RESULTADOS: Vinte e uma semanas após EAS: índice de massa (GE-IC>GE>GC,p<0.05); pressão sistólica: (GE-IC = GE>GC, p<0,05); pressão diastólica: (GE-IC>GE>GC, p<0,05); estresse meridional sistólico e diastólico: (GE-IC>GE>GC,p<0.05); área de secção dos miócitos: (GE-IC>GE>GC, p<0,05) e conteúdo de hidroxiprolina: (GE-IC>GE>GC, p<0,05) do VE. No grupo GE-IC o remodelamento geométrico do VE foi caracterizado por aumento significante das dimensões e espessura relativa da parede normal (remodelamento excêntrico) enquanto que o grupo GE apresentou remodelamento concêntrico. Os índices de desempenho do VE do grupo GE-IC foram significantemente menores que do grupo GE. CONCLUSÃO: Os grupos GE-IC e GE diferiram primariamente no processo de remodelação geométrica do VE e estrutural do miocárdio que estabeleceu um estado cronicamente compensado no grupo GE e precipitou a ICC no grupo GE-IC na vigência de graus equivalentes de comprometimento da contratilidade. Neste modelo experimental a fase de transição da hipertrofia compensada para a ICC está mais estreitamente relacionada com o remodelamento geométrico adverso do VE e estrutural do miocárdio do que com o grau de comprometimento da contratilidade.
OBJECTIVE: To evaluate the relative contribution of left ventricular (LV) geometric remodeling and of morphological and functional myocardial changes in rats with induced supravalvar aortic stenosis (SAS), in the transition from compensated hypertrophy to congestive heart failure (CHF). METHODS: Twenty one weeks after induction of SAS, the rats were classified as controls (CG, n=13), without congestive heart failure (SG, n=11), or with congestive heart failure (SG-HF, n=12). All groups were evaluated with echocardiographic, hemodynamic and morphological study of the myocardium. RESULTS: Twenty one weeks after SAS: mass index (SG-HF>SG>CG, p<0.05); systolic pressure (SG-HF= SG>CG, p<0.05); diastolic pressure (SG-HF>SG>CG, p<0.05); systolic and diastolic meridional stress (SG-HF>SG>CG, p<0.05); LV myocyte cross-sectional area (SG-HF>SG>CG, p<0.05) and hydroxyproline content (SG-HF>SG>CG, p<0.05). In the SG-HF group, LV geometric remodeling was characterized by a significant increase in dimensions and relative thickness of the normal wall (excentric remodeling), whereas the SG group presented a concentric remodeling. Indexes of LV performance in the SG-HF group were significantly lower than those of the SG group. CONCLUSION: The SG-HF and SG groups differed primarily in the LV geometric remodeling and structural myocardial remodeling process, which established a chronically compensated state in the SG group and triggered CHF in the SG-HF group in the presence of equivalent degrees of impaired contractility.
Subject(s)
Animals , Male , Rats , Aortic Stenosis, Supravalvular/complications , Aortic Stenosis, Supravalvular/physiopathology , Heart Failure , Hypertrophy, Left Ventricular/complications , Hypertrophy, Left Ventricular/physiopathology , Myocardial Contraction/physiology , Ventricular Remodeling/physiology , Disease Models, Animal , Echocardiography , Rats, WistarABSTRACT
Pressure overload diseases, such as valvular stenosis and systemic hypertension, manifest morphologically in patients as cardiac concentric hypertrophy. Prevention of cardiac remodeling due to increased pressure overload is important to reduce morbidity and mortality. Epigallocatechin-3 gallate (EGCG) is a major bioactive polyphenol present in green tea which has been found to be a nitric oxide-mediated vasorelaxant and to be cardioprotective in myocardial ischemia-reperfusion injury. Therefore, we investigated whether EGCG supplementation could reduce in vivo pressure overloadmediated cardiac hypertrophy. Cardiac hypertrophy was induced by suprarenal transverse abdominal aortic constriction (AC) in rats. Three weeks after AC surgery, heart to body weight ratio increased in the AC group by 34% compared to the sham group. EGCG administration suppressed the load-induced increase in heart weight by 69%. Attenuation of cardiac hypertrophy by EGCG was associated with attenuation of the increase in myocyte cell size and fibrosis induced by aortic constriction. Despite abolition of hypertrophy by EGCG, transstenotic pressure gradients did not change. Echocardiogram revealed that increased left ventricular systolic dimensions and deteriorated systolic function were relieved by EGCG. These results suggest that EGCG prevents the development of left ventricular concentric hypertrophy by pressure overload and may be a useful therapeutic modality to prevent cardiac remodeling in patients with pressure overload myocardial diseases.