Function In Chronic Heart Failure Rats Research Articles

Effect of moxibustion at "Xinshu" (BL15) and "Feishu" (BL13) on expression of TRPV1 and CGRP in the myocardial tissue of chronic heart failure rats.

To observe the effect of moxibustion at "Xinshu" (BL15) and "Feishu" (BL13) on transient receptor potential vanilloid type 1(TRPV1), calcitonin gene-related peptide (CGRP), and serum interleukin-10 (IL-10) in the myocardial tissue of rats with chronic heart failure (CHF), so as to explore its underlying mechanisms in improvement of CHF. Male SD rats were randomly divided into the normal, model, moxibustion, capsaicin, moxibustion + capsaicin, and moxibustion + solvent groups, with 10 rats in each group. The CHF model was established by permanent ligation of the anterior descending branch of the left coronary artery. Mild moxibustion was applied to bilateral BL13 and BL15 for 30 min once daily for 4 weeks. Rats in the capsaicin group were smeared with capsaicin in the acupoint area once a day for 4 weeks. For rats of the moxibustion + capsaicin and moxibustion + solvent groups, capsaicin and solvent were applied to the acupoint area before moxibustion for 4 weeks, respectively. The ejection fraction (EF) and left ventricular fractional shortening rate (FS) were examined by echocardiography. HE staining was used to observe the myecardial morphological structure. The mRNA and protein expression levels of TRPV1, CGRP and galectin-3 (Gal-3) in myocardial tissue were detected by real-time quantitative PCR and Western blot, respectively. The content of IL-10 in serum was detected by ELISA. After modeling, the pathological changes of myocardium (as cardiac muscle fiber disorder, inflammatory cell infiltration, etc.) were obvious, and the EF, FS, serum IL-10, protein and mRNA exspression of TRPV1 and CGRP were significantly decreased (P<0.01) in the model group compared with the normal group, while the protein and mRNA exspression of Gal-3 were significantly up-regulated (P<0.01). Following the interventions, the above-mentioned indexes were all reversed in moxibustion, capsaicin, and moxibustion + capsaicin groups (P<0.01), and the effect of moxibustion + capsaicin was the best (P<0.05, P<0.01). Moxibustion can reduce myocardial injury and improve cardiac function in CHF rats, which may be related to its effects in up-regulating the expression of TRPV1 and CGRP, and down-regulating the expression of Gal-3 to alleviate myocardial fibrosis.

Effect of moxibustion combined with intraperitoneal injection of benazepril on endoplasmic reticulum stress-related protein phosphorylation in rats with chronic heart failure.

To observe the effect of moxibustion at "Xinshu"(BL15) and "Feishu"(BL13) combined with intraperitoneal injection of benazepril on cardiac function and phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2α (elF2α) proteins in myocardium of rats with chronic heart failure (CHF), so as to explore its potential mechanism underlying improvement of CHF. A total of 42 male SD rats were randomly assigned to blank control (n=10), CHF model (n=7), medication (benazepril, n=8), moxibustion (n=8) and moxibustion+benazepril (n=9) groups, after cardiac ultrasound model identification and elimination of the dead. The CHF model was established by intraperitoneal injection of doxorubicin hydrochloride (DOX), once every week for 6 weeks. Mild moxibustion was applied to bilateral BL15 and BL13 regions for 20 min, once daily for 3 weeks. The rats of the medication group and moxibustion+benazepril group (benazepril was given first, followed by moxibustion) received intraperitoneal injection of benazepril (0.86 mg/kg) solution once daily for 3 weeks . The cardiac ejection fraction (EF) and left ventricular fractional shortening (FS) were measured using echocardiography. Histopathological changes of the cardiac muscle tissue were observed under light microscope after hematoxylin-eosin (H.E.) staining. Serum contents of B-type brain natriuretic peptide (BNP) and angiotensin Ⅱ (AngⅡ) were measured by enzyme-linked immunosorbent assay (ELISA). The expressions of phospho-PERK (p-PERK) and phospho-elF2α (p-elF2α) in the myocardium were detected by Western blot. Compared with the blank control group, the EF and FS of the left cardiac ventricle were significantly decreased (P<0.01), while the contents of serum BNP and AngⅡ, and expression levels of p-PERK and p-eIF2α significantly increased in the model group (P<0.01). In comparison with the model group, both the decreased EF and FS and the increased BNP and AngⅡ contents as well as p-PERK and p-elF2α expression levels were reversed by moxibustion, medication and moxibustion+benazepril (P<0.01). The effects of moxibustion+benazepril were markedly superior to those of simple moxibustion and simple medication in raising the levels of EF and FS rate and in down-regulating the contents of BNP, Ang Ⅱ, levels of p-PERK and p-elF2α (P<0.01, P<0.05). Outcomes of H.E. staining showed irregular arrangement of cardiomyocytes, cell swelling, vacuole and inflammatory infiltration in the model group, which was relatively milder in the 3 treatment groups. The effects of moxibustion+benazepril were superior to those of moxibustion or benazepril. Moxibustion combined with Benazepril can improve the cardiac function in CHF rats, which may be related to its functions in down-regulating the expression levels of myocardial p-PERK and p-elF2α to inhibit endoplasmic reticulum stress response.

HDAC3 Impairs Cardiac Function in Chronic Heart Failure Rats via Mediating MicroRNA-26b-3p to Target High Mobility Group AT-Hook 2.

Histone deacetylase 3 (HDAC3) has been studied in chronic heart failure (CHF), while the regulatory mechanism of HDAC3 on the development of CHF in regulating microRNA (miR)-26b-3p/high mobility group AT-hook 2 (HMGA2) axis has not been extensively investigated. This study aimed to probe the effects of HDAC3, miR-26b-3p and HMGA2 on CHF. CHF rat models were established using aortic coarctation. HDAC3, miR-26b-3p and HMGA2 levels in CHF rats were examined. Thereafter, the CHF rats were injected with relative oligonucleotides and plasmids of HDAC3, miR-26b-3p and HMGA2 to detect the cardiac function, inflammatory reaction, myocardial tissue pathological changes, and cardiomyocyte apoptosis. The binding relationship between miR-26b-3p and HMGA2 and the interaction between HDAC3 and miR-26b-3p were validated. HDAC3 and HMGA2 were elevated, while miR-26b-3p was decreased in CHF rats. The reduced HDAC3 or HMGA2 or enriched miR-26b-3p attenuated cardiac dysfunction, inflammatory reaction, myocardial tissue pathological changes and cardiomyocyte apoptosis in CHF rats, while the reduction of miR-26b-3p exerted the opposite effects. Furthermore, the inhibition of the miR-26b-3p or elevation of HMGA2 reversed the effect of reduced HDAC3 on mitigating CHF progression. Mechanically, miR-26b-3p targeted HMGA2 and HDAC3 bound to miR-26-3p. Downregulation of HDAC3 relieves cardiac function in CHF rats via mediating miR-26b-3p/HMGA2 axis. This study provides novel theory references and a distinct direction for the therapy strategies of CHF.

Effect of moxibustion combined with benazepril on expression of IL-18 and phosphorylated protein kinase B in myocardial tissue of rats with chronic heart failure

To observe the effect of moxibustion combined with benazepril on cardiac function and expression levels of myocardial interleukin-18(IL-18), phosphorylated protein kinase B(p-Akt) in rats with chronic heart failure (CHF), so as to explore its underlying mechanisms in improvement of CHF. Fifty male rats were randomly divided into normal, model, moxibustion, benazepril and moxibustion+benazepril groups (n=10 rats per group). The CHF model was established by intraperitoneal injection of doxorubicin hydrochloride solution (DOX, 2.5 mg/kg) twice a week for 4 weeks. After successful modeling, the rats in the normal and model groups were fed with normal diet, and fixed on a rat plate for 20 min each time without any treatment. Mild moxibustion was applied to bilateral "Feishu" (BL13) and "Xinshu" (BL15) for 20 min each time, for 3 weeks in the moxibustion and moxibustion+benazepril groups. Rats of the benazepril and moxibustion+benazepril groups received gavage of benazepril (2 mg/kg) once daily for 3 weeks. The general behaviors of rats were observed. The ejection fraction (EF), left ventricular diameter shortening (FS), left ventricular end-diastolic diameter (LVIDd), left ventricular end-systolic diameter (LVIDs), heart rate (HR) and ventricular septal thickness (IVS) were examined by echocardiography. The content of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) was detected by enzyme-linked immunosorbent assay, and expression levels of myocardial IL-18, p-Akt were detected by Western blot. Compared with the normal group, the EF, FS, IVS, and myocardial p-Akt expression level were significantly reduced (P<0.01), and the LVIDd, LVIDs, HR, and serum NT-proBNP content and myocardial IL-18 expression level were significantly increased in the model group (P<0.01). In comparison with the model group, the EF, FS, IVS, and myocardial p-Akt were remarkably up-regulated (P<0.05, P<0.01), and the LVIDd, LVIDs, HR, serum NT-proBNP content, and myocardial IL-18 expression level were significantly down-regulated (P<0.05, P<0.01) in the moxibustion, benazepril, and moxibustion+benazepril groups. Compared with the moxibustion+benazepr group, the levels of LVIDs, HR, serum NT-proBNP and myocardial IL-18 expression were obviously higher (P<0.05, P<0.01), while the levels of EF, FS, IVS and p-Akt were significantly lower in the moxibustion and benazepril groups (P<0.01). Moxibustion combined with benazepril improves cardiac function in CHF rats, and is superior to simple moxibustion and simple benazepril in reducing IL-18 expression and increasing p-Akt expression in myocardial tissue.

Paeoniflorin Attenuates Myocardial Fibrosis in Isoprenaline-induced Chronic Heart Failure Rats via Inhibiting P38 MAPK Pathway.

Paeoniforin (Pae) is a monoterpenoid glycoside compound and has many biological activities, such as immunosuppression, anti-inflammation and anti-cell proliferation. However, the effects and mechanisms of Pae on chronic heart failure (CHF) remain unclear. This study was conducted to assess the effects and mechanisms of Pae on myocardial fbrosis in isoprenaline (Iso)-induced CHF rats. Pae (20 mg/kg) was intragastrically administrated to CHF rats for 6 weeks. Cardiac structure and function were assessed. The protein and mRNA levels of transforming growth factor β1 (TGF-β1) and p38 were detected. Compared to Iso group, Pae could alleviate myocardial fibrosis and improve cardiac function in CHF rats. The levels of collagen volume fraction (13.75%±3.77% vs. 30.97%±4.22%, P<0.001) and perivascular collagen volume area (14.32%±2.50% vs. 28.31%±3.16%, P<0.001) were signifcantly reduced in Pae group as compared with those in Iso group. The expression of TGF-β1 protein (0.30±0.07 vs. 0.66±0.07, P<0.05) and mRNA (3.51±0.44 vs. 7.58±0.58, P<0.05) decreased signifcantly in Pae group as compared with that in Iso group. The expression of p38 protein (0.36±0.12 vs. 0.81±0.38, P<0.05) and mRNA (3.84±0.05 vs. 4.40±0.17, P<0.05) also decreased markedly in Pae group as compared with that in Iso group. Pae could attenuate myocardial fbrosis and improve cardiac function in CHF rats by down-regulating the p38 MAPK signaling pathway.

Effect of paeoniflorin on cardiac remodeling in chronic heart failure rats through the transforming growth factor β1/Smad signaling pathway.

Cardiac remodeling is an important mechanism for the occurrence and development of chronic heart failure (CHF). Paeoniflorin (Pae) is the main active ingredient of Chinese herbaceous peony and has novel anti-inflammatory effect. This study was conducted to assess the effects and mechanisms of Pae on cardiac remodeling in CHF rats. A cardiac remodeling rat model was induced by isoprenaline (Iso). Pae (20 µg/kg/d) was administrated to CHF rats for six weeks. Cardiac ultrasound was used to assess the structure and function of CHF rats. Collagen volume fraction (CVF) and perivascular collagen volume area of myocardial tissues were calculated. With real-time polymerase chain reaction and Western blot, the protein and mRNA levels of transforming growth factor β1 (TGF-β1) and Smad3 were detected. Compared to Iso group, Pae can alleviate cardiac remodeling and improve cardiac function in CHF rats. The levels of CVF and perivascular collagen volume area reduced in Pae group (P<0.05). The expression of TGF-β1 and Smad3 protein decreased in Pae and Cap group (P<0.05). Further, the expression of TGF-β1 and Smad3 mRNA also decreased markedly in the Pae group (P<0.05). Pae could attenuate cardiac remodeling and improve cardiac function in CHF rats. The potential mechanism for the cardioprotective effect of Pae may be highly associated with the down-regulating of TGF-β1/Smad signaling pathway.

Moxibustion improves cardiac function by up-regulating autophagy-related proteins of cardiomyocytes in rats with chronic heart failure

To observe the effect of moxibustion on cardiac function and the expression of autophagy-related proteins microtubule-associated protein 1 light chain 3 (LC3) and selective autophagy receptor signaling adaptor sequestosome 1 (SQSTM1/p62) in rats with chronic heart failure (CHF), so as to explore its underlying mechanisms in preventing and treating CHF. Sixty male SD rats were randomly divided into normal, model, moxibustion, autophagy inhibitor 3-methyladenine (3-MA) and autophagy agonist rapamycin (RAPA) groups (n＝12 rats/group). The CHF model was established by intrape-ritoneal injection of adriamycin (ADR, 2 mg/kg, once every week for 12 weeks). Mild moxibustion was applied to bilateral "Feishu" (BL13) and "Xinshu" (BL15) for 20 min every time. Rats of the 3-MA group were treated by intraperitoneal injection of 3-MA suspension (15 mg/kg), and those of the RAPA group treated by gavage of RAPA suspension (2 mg/kg). All the treatments were given once a day for 3 weeks. The heart rate (HR), cardiac output (CO), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and maximum rising and lowering rates of left ventricular pressure (±dp/dtmax) were measured for assessing the cardiac performance. Histopathological changes of the left ventricular myocardium were observed by HE staining. The expression levels of LC3-Ⅰ， LC3-Ⅱ and p62 proteins of the left ventricle myocardium tissue were detected by Western blot. After modeling, the pathological changes of myocardium (as myocardial cell swelling with vacuoles, myocardial fibre breakage, etc.) were obvious, and the HR, LVEDP, LC3-Ⅱ and LC3-Ⅱ/Ⅰ protein expression levels were significantly increased in the model group compared with the normal group (P<0.01), while the CO, LVSP, ±dp/dtmax, and the expression of p62 protein were significantly down-regulated (P<0.01). Following the interventions, the myocardial injury was reduced, the HR, LVEDP, LC3-Ⅱ and LC3-Ⅱ/Ⅰ levels in both moxibustion and 3-MA groups were significantly decreased (P<0.05, P<0.01), while the CO, LVSP, ±dp/dtmax and p62 expression level were significantly increased relevant to the model group (P<0.05, P<0.01). In addition, the ratio of LC3-Ⅱ/Ⅰ was significantly increased, and the expression level of p62 significantly down-regulated in the RAPA group compared with the model group (P<0.01). Moxibustion can improve cardiac function in CHF rats, which may be related to its effects in down-regulating the ratio of LC3-Ⅱ/Ⅰ and up-regulating the expression of p62 protein to inhibit cardiomyocyte autophagy.

Effects of Moxibustion on Ventricular Mass Index and Expression of Apoptosis Related Proteins in Myocardium of Rats with Chronic Heart Failure

To observe the effect of moxibustion on cardiac function and the expression of B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax), Fas, Fas ligand (FasL) in cardiomyocytes of chronic heart failure (CHF) rats, so as to explore its underlying mechanisms in preventing and treating CHF. SD rats were randomly divided into normal control, model, moxibustion, Captopril and moxibustion ＋ Captopril (M＋C) groups (n＝12 rats/group). The CHF model was established by intraperitoneal injection of Adriamycin (ADR, from 1 to 4 mg/kg, once every other day for 15 days). Mild moxibustion was applied to bilateral"Feishu"(BL 13) and "Xinshu"(BL 15). Rats of the Captopril group was treated by gavage of Captopril suspension (5 mg/mL, 25 mL/kg), and those of the M＋C group treated by the combined two methods. All the treatments were given once a day for 3 weeks. The general conditions and behaviors of rats were observed. The left ventricular mass index (LVMI) and right ventricular mass index (RVMI) were detected for assessing the cardiac performance. Morphological changes of myocardium were observed by HE staining. Enzyme linked immunosorbent assay (ELISA) was used to detect the concentrations of B-type natriuretic peptide (BNP) and precursor N-terminal pro-brain natriuretic peptide (NT-pro BNP) in the serum. The expression levels of Bcl-2, Bax, Fas and FasL of the left ventricle of heart were detected by Western blot. After modeling, the pathological changes of myocardium (as myocardial cell swelling with vacuoles, myocardial fibre breakage, etc.) were obvious, the LVMI, RVMI, serum BNP and NT-pro BNP concentrations, and myocardial Bax, Fas and FasL protein expression levels were significantly increased in the model group compared with the normal group (P<0.01), while the expression level of Bcl-2 was significantly down-regulated (P<0.01). Following the interventions, the myocardial injury was reduced, both LVMI and RVMI, serum BNP concentration and Bax, Fas and FasL expression levels in the three treatment groups, and serum NT-pro BNP concentration in the moxibustion and M＋C groups were significantly decreased (P<0.05, P<0.01), while the myocardial Bcl-2 protein levels in the three treatment groups were significantly increased relevant to the model group (P<0.01). Comparison among the three treatment groups showed that the effects of moxibustion ＋ Captopril were significantly superior to those of simple moxibustion and simple Captopril in suppressing CHF-induced increased expression of myocardial Bax, Fas and FasL, and in lessening CHF-induced decrease of Bcl-2 level (P<0.05, P<0.01). No significant differences were found among the three treatment groups in down-regulating LVMI and RVMI, and serum BNP content (P>0.05)．. Moxibustion can reduce myocardial injury and improve cardiac function in CHF rats, which may be related to its effects in down-regulating the expression of myocardial Bax, Fas and FasL proteins, and up-regulating the expression of Bcl-2 protein to inhibit cardiomyocyte apoptosis.

X indening oral liquid improves cardiac function of rats with chronic cardiac failure via TGF-ß1/Smad3 and p38 MAPK pathway.

Objective:Xindening oral liquid (Xin) is a widely used traditional Chinese medicine for the treatment of chronic heart failure (CHF). However, the exact mechanisms related to its therapeutic effects against CHF remain unclear. In the present study, we investigate the effects of Xin on cardiac function in CHF rats and the possible mechanisms involved.Methods:Transverse aortic constriction (TAC) was conducted to induce a CHF rat model in this study. Sixty male Wistar rats were randomly assigned to six groups 28 days after TAC: sham; CHF model; Xin at concentrations of 5 ml/kg, 10 mL/kg, and 20 mL/kg; and QiLi 0.6 g/kg. After four weeks, the rats were treated with Xin (5, 10, or 20 mL/kg/d) for six weeks consecutively. At the end of the study, the cardiac function, heart weight index (HWI) and left ventricular mass index (LVMI), serum level of LDH, B-type natriuretic peptide (BNP), cTnI and CK-MB, and collagen volume fraction were studied. The expression of transforming growth factor-b1 (TGF-b1), drosophila mothers against decapentaplegic protein 3 (Smad3), and p38 mitogen activated protein kinase (p38 MAPK) were detected.Results:The results showed that Xin treatment significantly improved cardiac function but decreased the serum level of LDH, BNP, cTnI, and CK-MB of CHF rats. In addition, it reduced the HWI, LVMI, and collagen volume fraction compared with the model group. Xin treatment significantly improved cardiac function and attenuated cardiac fibrosis by suppressing the p38 MAPK and TGF-b1/Smad3 signaling pathway in CHF rats.Conclusion:These results suggested that Xin might be a promising complementary treatment for CHF. More detailed experimental studies will be carried out in our subsequent research.

Electrical stimulation of the aortic depressor nerve in conscious rats overcomes the attenuation of the baroreflex in chronic heart failure.

Chronic heart failure (CHF) is characterized by autonomic dysfunction combined with baroreflex attenuation. The hypotensive and bradycardic responses produced by electrical stimulation of the aortic depressor nerve (ADN) were examined in conscious CHF and control male Wistar rats (12-13 wk old). Furthermore, the role of parasympathetic and sympathetic nervous system in mediating the cardiovascular responses to baroreflex activation was evaluated by selective β1-adrenergic and muscarinic receptor antagonists. CHF was induced by myocardial infarction. After 6 wk, the subjects were implanted with electrodes for ADN stimulation. Twenty-four hours later, electrical stimulation of the ADN was applied for 20 s using five different frequencies (5, 15, 30, 60, and 90 Hz), while the arterial pressure was recorded by a catheter implanted into the femoral artery. Electrical stimulation of the ADN elicited progressive and similar hypotensive and bradycardic responses in control (n = 12) and CHF (n = 11) rats, while the hypotensive response was not affected by methylatropine. Nevertheless, the reflex bradycardia was attenuated by methylatropine in control, but not in CHF rats. Atenolol did not affect the hypotensive or bradycardic response in either group. The ADN function was examined under anesthesia through electroneurographic recordings. The arterial pressure-ADN activity relationship was attenuated in CHF rats. In conclusion, despite the attenuation of baroreceptor function in CHF rats, the electrical stimulation of the ADN elicited a stimulus-dependent hypotension and bradycardia of similar magnitude as observed in control rats. Therefore, electrical activation of the aortic baroreflex overcomes both the attenuation of parasympathetic function and the sympathetic overdrive.

Effect of angiotensin II on voltage-gated sodium currents in aortic baroreceptor neurons and arterial baroreflex sensitivity in heart failure rats.

Impairment of arterial baroreflex sensitivity is associated with mortality in patients with chronic heart failure (CHF). Elevation of plasma angiotension II (Ang II) contributes to arterial baroreflex dysfunction in CHF. A reduced number of voltage-gated sodium (Nav) channels in aortic baroreceptor neurons are involved in CHF-blunted arterial baroreflex. In this study, we investigated acute effect of Ang II on Nav currents in the aortic baroreceptor neuron and on arterial baroreflex in sham and coronary artery ligation-induced CHF rats. Using Ang II I radioimmunoassay, real-time reverse transcription-PCR and western blot, we found that Ang II levels, and mRNA and protein expression of angiotension II type 1 receptor in nodose ganglia from CHF rats were higher than that from sham rats. Local microinjection of Ang II (0.2 nmol) into the nodose ganglia decreased the arterial baroreflex sensitivity in sham rats, whereas losartan (1 nmol, an angiotension II type 1 receptor antagonist) improved the arterial baroreflex sensitivity in CHF rats. Data from patch-clamp recording showed that Ang II (100 nmol/l) acutely inhibited Nav currents in the aortic baroreceptor neurons from sham and CHF rats. In particular, inhibitory effect of Ang II on Nav currents in the aortic baroreceptor neurons was larger in CHF rats than that in sham rats. Losartan (1 μmol/l) totally abolished the inhibitory effect of Ang II on Nav currents in sham and CHF aortic baroreceptor neurons. These results suggest that elevation of endogenous Ang II in the nodose ganglia contributes to impairment of the arterial baroreflex function in CHF rats through inhibiting Nav channels.

Interval and continuous exercise enhances aerobic capacity and hemodynamic function in CHF rats.

OBJECTIVE: The aim of the present study was to compare the effects of continuous versus interval aerobic exercise training on hemodynamic parameters, cardiac remodeling, and maximal exercise capacity (MEC) in chronic heart failure (CHF) rats. METHOD: Twenty-four male Wistar rats were subjected to myocardial infarction (MI) surgery. Five weeks post MI, the animals were assigned to one of three groups: sedentary group (CHF-Sed, n=8), aerobic continuous training group (CHF-ACT, n=8), and aerobic interval training group (CHF-AIT, n=8). Treadmill training was performed five times a week for 8 weeks (ACT: 50 min/day at 15 m/min and AIT: 40 min/day with 8 min of warm-up at 10 m/min and exercise at 15 m/min 4×4 min interspersed with 4×4 min at 23 m/min). MEC was evaluated pre and post exercise program. RESULTS: Left ventricular end-diastolic pressure (LVEDP), left ventricular mass/body mass ratio (LVM:BM), and total collagen volume fraction were lower in the trained groups compared with the sedentary group, but no difference was found between the trained groups. Systolic ventricular pressure (SVP) and maximum positive derivative of LV pressure (+dP/dtmax) were higher in the trained groups, but CHF-ACT showed higher +dP/dtmax compared to CHF-AIT. Both training regimens were able to increase MEC. However, the aerobic interval training was superior for improving MEC. CONCLUSION: Aerobic training is an important intervention to improve cardiac function and remodeling and physical capacity in CHF rats. Interval training is a potential strategy to maximize the results, but exercise type and intensity are still topics to be explored.

Effects of Qili Qiangxin Capsule on AQP2, V2R, and AT1R in Rats with Chronic Heart Failure.

Qili qiangxin capsule (QL), a traditional Chinese herbal compound, has been proved to be effective and safe for the treatment of chronic heart failure (CHF). Upregulation of aquaporin-2 (AQP2) accounts for the water retention in CHF. The aim of the present study was to evaluate the effects of QL on the expression of AQP2 in rats with CHF induced by acute myocardial infarction and to investigate the underlying mechanisms. The urine output of all rats was quantified and collected every day at the first week and the 4th week after administration of QL or Valsartan. The expression of AQP2, vasopressin type 2 receptor (V2R), and angiotensin II type 1 receptor (AT1R) were examined after treatment for 4 weeks. Urinary output increased significantly after administration of QL. Importantly, the protein expression of AQP2 and AQP2 phosphorylated at serine 256 (pS256-AQP2) was downregulated after administration of QL and Valsartan to CHF rats. Furthermore, QL reduced plasma arginine vasopressin (AVP) and angiotensin II (AngII) level and downregulated V2R and AT1R protein expression. Thus, QL exerts its diuretic effect and improves cardiac function in CHF rats by reversing the increases in both AQP2 and pS256-AQP2 expression. The possible mechanisms may involve inhibition of V2R and AT1R.

Sclederma of Poria cocos exerts its diuretic effect via suppression of renal aquaporin-2 expression in rats with chronic heart failure

Ethnopharmacological relevanceSclederma of Poria cocos (Hoelen) has been used as a diuretic in traditional Asian medicine. However, the underlying mechanism by which Sclederma of Poria cocos (hoelen) exerts its diuretic effect has not been well identified. The aim of the present study was to evaluate the effects of Sclederma of Poria cocos (hoelen) in rats with chronic heart failure (CHF) induced by acute myocardial infarction and to investigate the underlying mechanisms. Materials and methodsAn aqueous extract of Sclederma of Poria cocos (hoelen) (2.4g/kg/d, 1.2g/kg/d or 0.6g/kg/d) or furosemide (20mg/kg/d) was administered orally to male Sprague-Dawley rats starting on the day of coronary ligation. The urine output of all rats was quantified and collected every day for 1 or 4 weeks. The expression of aquaporin-2 (AQP2) was examined after treatment for 1 or 4 weeks. ResultsUrinary output increased significantly and urinary osmolality decreased after oral administration of Sclederma of Poria cocos (hoelen) for both 1 and 4 weeks. Sclederma of Poria cocos (hoelen) caused less electrolyte disorder than furosemide. Furthermore, Sclederma of Poria cocos (hoelen) reduced the levels of plasma BNP in CHF rats, whereas furosemide had no effect. Importantly, both mRNA and protein expression of AQP2 were down-regulated and urinary excretion of AQP2 was decreased after administration of Sclederma of Poria cocos (hoelen) to CHF rats. Similarly, Sclederma of Poria cocos (hoelen) reduced plasma arginine vasopressin (AVP) level and down-regulated vasopressin type 2 receptor (V2R) mRNA expression. ConclusionsSclederma of Poria cocos (hoelen) exerts its diuretic effect and improves cardiac function in CHF rats via the AVP-V2R-AQP2 axis.

Effects of Pentoxifylline on Exercising Skeletal Muscle Vascular Control in Rats with Chronic Heart Failure

Purpose : Chronic heart failure (CHF) is hallmarked by cardiac and peripheral vasculature dysfunction which has been associated with elevations in tumor necrosis factor-α (TNF-α) and exercise intolerance. The pharmaceutical TNF-α synthesis suppressor pentoxifylline (PTX) reduces plasma [TNF-α] and improves left ventricular (LV) function in CHF rats, but the effects of PTX on skeletal muscle blood flow (BF) and vascular conductance (VC) during exercise are unknown. We tested the hypothesis that PTX would elevate skeletal muscle BF and VC at rest and during submaximal treadmill exercise in CHF rats and improve exercise tolerance and peak O 2 uptake. Methods : CHF rats (coronary artery ligation) received i.p. injections of 30 mg·kg -1 ·day -1 of PTX (CHF+PTX, n=13) or saline (CHF, n=8) for 21 days. BF was measured using radiolabeled microspheres at rest and during exercise (treadmill, 20 m/min -1 , 5% grade). Results : Resting and exercising mean arterial pressures (MAP) were greater in CHF+PTX compared to CHF (i.e., closer to expected healthy values, both p<0.05). During exercise PTX increased total hindlimb BF (CHF: 83±9, CHF+PTX: 114±8 ml·min -1 ·100g -1 , p<0.05) and VC (CHF: 0.75±0.08, CHF+PTX: 0.88±0.06 ml·min -1 ·100g -1 ·mmHg -1 , p<0.05). Furthermore, exercising BF was increased in 21 and VC in 11, of the 28 individual hindlimb muscles or muscle parts with no apparent fiber-type specificity. Conclusions : PTX administration augments skeletal muscle BF and VC during locomotory exercise in CHF rats, but the lack of increased exercise tolerance or peak O 2 uptake suggest continued peripheral O 2 pathway dysfunction.

In Vivo Transfection of Manganese Superoxide Dismutase Gene or Nuclear Factor κB shRNA in Nodose Ganglia Improves Aortic Baroreceptor Function in Heart Failure Rats

Arterial baroreflex sensitivity is attenuated in chronic heart failure (CHF) state, which is associated with cardiac arrhythmias and sudden cardiac death in patients with CHF. Our previous study showed that CHF-induced sodium channel dysfunction in the baroreceptor neurons was involved in the blunted baroreflex sensitivity in CHF rats. Mitochondria-derived superoxide overproduction decreased expression and activation of the sodium channels in the baroreceptor neurons from CHF rats. However, the molecular mechanisms responsible for the sodium channel dysfunction in the baroreceptor neurons from CHF rats remain unknown. We tested the involvement of nuclear factor κB (NFκB) in the sodium channel dysfunction and evaluated the effects of in vivo transfection of manganese superoxide dismutase gene and NFκB shRNA on the baroreflex function in CHF rats. CHF was developed at 6 to 8 weeks after left coronary artery ligation in adult rats. Western blot and chromatin immunoprecipitation data showed that phosphorylated NFκB p65 and ability of NFκB p65 binding to the sodium channel promoter were increased in the nodose ganglia from CHF rats. In vivo transfection of adenoviral manganese superoxide dismutase gene or lentiviral NFκB p65 shRNA into the nodose ganglia partially reversed CHF-reduced sodium channel expression and cell excitability in the baroreceptor neurons and improved CHF-blunted arterial baroreflex sensitivity. Additionally, transfection of adenoviral manganese superoxide dismutase also inhibited the augmentation of phosphorylated NFκB p65 in the nodose neurons from CHF rats. The present study suggests that superoxide-NFκB signaling contributes to CHF-induced baroreceptor dysfunction and resultant impairment of baroreflex function.

In‐vivo transfection of manganese SOD gene and NFkB shRNA into nodose ganglia improve blunted baroreflex sensitivity in chronic heart failure rats

Blunted baroreflex sensitivity is observed in chronic heart failure (CHF) patients and animals. Our previous study has shown that mitochondria‐derived superoxide‐NFκB signaling reduces the Nav channel activation in baroreceptor neurons. Additionally, reduced Nav channel activiation contributes to the impairment of baroreflex sensitivity in the CHF state. Using in‐vivo gene transfection technique in present study, we examined the effect of Adenoviral Manganese SOD (Ad.MnSOD) and lentiviral NFκB p65 shRNA on the attenuated baroreflex function in CHF rats. CHF were induced by left coronary ligation. CHF significantly elevated mitochondrial superoxide and NFκB p65 expression in nodose neurons, and blunted baroreflex sensitivity. Ad.MnSOD transfection (4×107 PFU) into the nodose ganglia (NG) decreased CHF‐enhanced mitochondrial superoxide and NFκB p65 expression in nodose neurons, and improved baroreflex sensitivity in CHF rats. Similarly local transfection of lentivial NF‐κB p65 shRNA (5×103 IFU) into the NG also improved baroreflex sensitivity in CHF rats. These results suggest that mitochondrial superoxide‐NFκB signaling is involved in the impairment of baroreflex function in CHF rats.

RbAp48 and 46 Disassociate GATA4 from p300 and Inhibit Hypertrophy-responsive Gene Transcription in Cardiomyocytes

cardiovasculature of rats with chronic heart failure (CHF). Methods and Results: Male Sprague-Dawley rats underwent left coronary artery ligation (LCAL) to induce CHF, and were randomly assigned to sedentary or treadmill exercise groups at 4 weeks after the LCAL. Exercise training for 4weeks improved cardiac and renal function in CHF rats, as indicated by echocardiographic data, plasma brain natriuretic peptide (BNP) and creatinine clearance. The NOS activity and expression of eNOS, nNOS protein were significantly decreased in the left ventricle, renal cortex, outer medulla and inner medulla of CHF rats, and exercise training markedly increased the NOS activity and expressions in those tissues of CHF rats. Conclusion: Exercise training improves cardiac and renal function in CHF rats through upregulating the NOS activity and eNOS, nNOS expressions in the kidney in addition to in the cardiovasculature. The beneficial effects of exercise training in CHF may be mediated in part by upregulation of the NOS in the kidney.