Cardiac hypertrophy is a common pathological process of various cardiovascular diseases and eventually develops into heart failure. This paper was aimed to study the different pathological characteristics exhibited by different mouse strains after hypertrophy stimulation. Two mouse strains, A/J and FVB/nJ, were treated with isoproterenol (ISO) by osmotic pump to induce cardiac hypertrophy. Echocardiography was performed to monitor heart morphology and function. Mitochondria were isolated from hearts in each group, and oxidative phosphorylation function was assayed in vitro. The results showed that both strains showed a compensatory enhancement of heart contractile function after 1-week ISO treatment. The A/J mice, but not the FVB/nJ mice, developed significant cardiac hypertrophy after 3-week ISO treatment as evidenced by increases in left ventricular posterior wall thickness, heart weight/body weight ratio, cross sectional area of cardiomyocytes and cardiac hypertrophic markers. Interestingly, the heart from A/J mice contained higher mitochondrial DNA copy number compared with that from FVB/nJ mice. Functionally, the mitochondria from A/J mice displayed faster O
Animals ; Cardiomegaly/chemically induced* ; Heart Failure ; Isoproterenol/toxicity* ; Mice ; Mitochondria ; Myocytes, Cardiac/metabolism*

OBJECTIVETo explore the effect of extracellular signal regulated kinase 1/2 (ERK1/2) on edaravone (EDA)-triggered protection against myocardial toxicity induced by isoprenaline (ISO) in H9c2 myocardial cells (H9c2 cells).

METHODSH9c2 cells were exposed to ISO at different concentrations to establish a cardiac toxicity model induced by persistent excitation of β1 receptor. EDA was added before ISO as a pretreatment. PD-98059, an ERK1/2 inhibitor, was administered 1 h prior to EDA to inhibit the phosphorylation of ERK1/2. Cell viability was measured using cell counter kit (CCK-8). The expressions of p-ERK1/2 and t-ERK1/2 were tested by Western blotting. Mitochondrial membrane potential (MMP) was detected by Rhodamine123 (Rh123) staining and photofluorography.

RESULTSExposure of H9c2 cells to 80 µmol/L ISO for 24 h down-regulated ERK1/2 phosphorylation and repressed MMP. Pretreatment with 10-40 µmol/L EDA for 1 h inhibited ISO-induced myocardial toxicity and pretreatment of 40 µmol/L EDA partially rescued ERK1/2 phosphorylation and MMP level. PD-98059 abolished cardiac protection of EDA, leading to myocardial toxicity and MMP loss.

CONCLUSIONEDA can protect H9c2 cells against myocardial injury induced by ISO by suppressing ISO-triggered inhibition of ERK1/2 activation.

Animals ; Antipyrine ; analogs & derivatives ; pharmacology ; Cell Line ; Flavonoids ; pharmacology ; Isoproterenol ; toxicity ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinase 3 ; metabolism ; Myocytes, Cardiac ; drug effects ; metabolism ; Phosphorylation ; Rats

BACKGROUNDPeroxisome proliferator-activated receptor (PPAR) alpha is one of the subtypes of PPARs. It regulates metabolism of lipid and lipoprotein, as well as glucose homeostasis. In addition, PPARalpha influences cellular proliferation, inflammation, differentiation and apoptosis, which plays a vital role in cardiovascular diseases. The purpose of this study was to investigate the role and mechanisms of PPARa activation in relation to acute myocardial damage induced by isoproterenol in rats.

METHODSThirty male Wister rats were randomly divided into control group, isoproterenol (Iso) injured group and fenofibrate (FF) treatment group. Acute myocardial damage caused by isoproterenol intraperitoneal injection induced ischemia was established. We determined the levels of creatine kinase (CK) and lactic dehydrogenase (LDH) in serum as well as the concentrations of free fatty acids (FFA) in serum and myocardium. The mRNA expressions of PPARa, muscular type carnitine palmitransferase (M-CPT-I) and medium chain lipid acetyl coenzyme A dehydrogenase (MCAD) were analyzed by reverse transcription-polymerase chain reaction (RT-PCR).

RESULTSCompared with the control group, the levels of serum CK and LDH were significantly increased after FF and Iso treatments. Moreover, the concentrations of FFA in both serum and myocardium were obviously increased in the Iso group and FF group, while the mRNA expressions of PPARalpha, M-CPT-I and MCAD declined, respectively (P < 0.01). When compared with the Iso group, significant decreases in serum CK and LDH were observed in the FF group. The concentrations of FFA both in serum and myocardial tissue were markedly decreased in the FF group, while the expressions of PPARalpha, M-CPT-I and MCAD mRNA were increased (vs. Iso, P < or = 0.01).

CONCLUSIONSThe utilization of FFA was reduced in isoproterenol induced acute myocardial damage. PPARalpha activation by its activator fenofibrate may play a key role in energy metabolism in acute myocardial damage induced by isoproterenol in rats.

Animals ; Creatine Kinase ; blood ; Energy Metabolism ; Fatty Acids, Nonesterified ; metabolism ; Fenofibrate ; pharmacology ; Heart ; drug effects ; Isoproterenol ; toxicity ; L-Lactate Dehydrogenase ; blood ; Male ; PPAR alpha ; physiology ; Rats ; Rats, Wistar

OBJECTIVETo investigate the protect effects of sodium ferulate (SF) on the daunormbicin(DNR-induced cardiotoxicity in juvenile rats.

METHODSForty male juvenile SD rats were randomly divided into control group (Control), daunorubicin group (DNR), sodium ferudate treatment group (DNR + SF), sodium ferudate group (SF) (n = 10) . Juvenile rats were intraperitoneally treated with DNR (2.5 mg/kg every week for a cumulative dose of 10 mg/kg) preparation immature myocardial injury model in presence with SF (60 mg/kg) oral treat- ment for 25 days. The left ventricular pressure and its response to isoproterenol were measured using left ventricular catheter. Rat myocardium myocardial pathology specimens and ultrastructure changes were also observed. The expression of cardiac Troponin I (cTNI) was detected by Western blot and RT-PCR. Results: SF treatment could inhibit the decreasing of heart rates induced by DNR damage (P < 0.05); it could increase the left ventrivular end diastolic pressure(LVEDP), heart rate, the maximal left ventrivular systolic speed(LVP + dp/dtmax) and the maximal left ventrivular diastolic speed (LVP-dp/dtmax) responding to isoproterenol stimulation(P < 0.01); SF also could improve the myocardial ultrastructure injuries and inhibit the decreasing of cTNI expression caused by DNR damages (P < 0.05).

CONCLUSIONSF treatment could alleviate the decreasing of cardiac reservation induced by DNR damages in juvenile rats, which might be related to its reversing the effects on the cardiac systolic and diastolic function injuries and its inhibiting effects on the decreasing of cTNI expression caused by DNR. The mechanism of SF preventing daunorubicin-induced cardiotoxicity in juvenile rats is relevant to inhabited cardiac Troponin I expression.

Animals ; Blood Pressure ; Cardiotoxicity ; drug therapy ; Coumaric Acids ; pharmacology ; Daunorubicin ; toxicity ; Heart ; physiopathology ; Heart Rate ; Isoproterenol ; Male ; Myocardium ; pathology ; Protective Agents ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Troponin I ; metabolism

BACKGROUNDMaintenance of normal cardiac function is controlled by the autonomic nervous system. In congestive heart failure (CHF), sympathetic nerve denervation is increasingly recognized. The sympathetic fiber density depends on the balance between neurotrophins and neural guidance molecules. Semaphorin 3A (sema3a), a secreted neural guidance factor, is a well characterized member of the newly found semaphorin family. It can induce sympathetic growth cone collapse and axon repulsion. We conducted this study to investigate cell sources of sema3a in the heart, the expression level of sema3a in CHF and discuss the possible role of sema3a in CHF.

METHODSRats were divided into four groups: 30 days control group rats, 30 days CHF rats, 60 days control group rats, 60 days CHF rats. The heart failure model was induced by injection of isoproterenol (ISO) 340 mg/kg continuously two days. All animals underwent echocardiography and haemodynamics measurements. Cardiac expression of sema3a was determined by real time polymerase chain reaction (RT-PCR) and Western blotting analysis. Immunohistochemical analysis was used to determine the cell source of sema3a in the heart.

RESULTSIsoproterenol induced 30 days and 60 days CHF rats displayed left ventricular dilation, systolic and diastolic function decrease. Sema3a was secreted by the cardiocytes and increased significantly in 30 days and 60 days CHF rats compared with the controls (RT-PCR: 30 days group: 0.32 ± 0.05 vs. 0.58 ± 0.06, P < 0.01; 60 days group: 0.34 ± 0.08 vs. 0.71 ± 0.07, P < 0.01. Western blotting: 30 days group: 0.25 ± 0.10 vs. 0.46 ± 0.10, P < 0.05; 60 days group: 0.29 ± 0.10 vs. 0.55 ± 0.16, P < 0.01. Immunohistochemical analysis: 30 days group: 2.91 ± 0.20 vs. 5.31 ± 0.30, P < 0.01; 60 days group: 2.94 ± 0.30 vs. 5.80 ± 0.30, P < 0.01).

CONCLUSIONSSema3a was expressed in the heart by cardiocytes. Increased expression of sema3a may partly account for sympathetic denervation in CHF; modulation of this pathway may prove beneficial in heart failure sympathetic remodeling.

Animals ; Blotting, Western ; Echocardiography ; Heart Failure ; chemically induced ; metabolism ; Hemodynamics ; drug effects ; Immunohistochemistry ; Isoproterenol ; toxicity ; Male ; Myocardium ; metabolism ; Rats ; Rats, Wistar ; Real-Time Polymerase Chain Reaction ; Semaphorin-3A ; genetics ; metabolism

Silibinin is a polyphenolic flavanoid derived from fruits and seeds of milk thistle (Silybum marianum). To investigate the effect and mechanism of silibinin on beta-isoproterenol-induced rat neonatal cardiac myocytes injury, the viability, the activation of lactate dehydrogenase (LDH) and the content of maleic dialdehyde (MDA) were chosen for measuring the degree of cardiac myocytes injury. Superoxide dismutase (SOD) activity, mitochondrial membrane potential (deltapsi) detected by flow cytometric analysis, and Western blotting analysis were applied to determine the related proteins. Silibinin protected isoproterenol-treated rat cardiac myocytes from death and significantly decreased LDH release and MDA production. Silibinin increased superoxide dismutase (SOD) activity, and increased mitochondrial membrane potential (deltapsi). Furthermore, the release of pro-apoptotic cytochrome c from mitochondria was reduced by silibinin. Silibinin increased the expression of anti-apoptotic Bcl-2 family protein Bcl-2, and up-regulation of SIRT1 inhibited the translocation of Bax from cytoplasm to mitochondria, which caused mitochondrial dysfunction and cell injury. Silibinin protects cardiac myocytes against isoproterenol-induced injury through resuming mitochondrial function and regulating the expression of SIRT1 and Bcl-2 family members.
Animals ; Animals, Newborn ; Blotting, Western ; Cardiotonic Agents ; isolation & purification ; pharmacology ; Cell Survival ; drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Isoproterenol ; toxicity ; L-Lactate Dehydrogenase ; metabolism ; Malondialdehyde ; metabolism ; Membrane Potential, Mitochondrial ; drug effects ; Milk Thistle ; chemistry ; Mitochondria, Heart ; drug effects ; metabolism ; physiology ; Myocytes, Cardiac ; drug effects ; metabolism ; pathology ; Plants, Medicinal ; chemistry ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Rats, Sprague-Dawley ; Silymarin ; isolation & purification ; pharmacology ; Sirtuin 1 ; Sirtuins ; metabolism ; Superoxide Dismutase ; metabolism ; Up-Regulation ; bcl-2-Associated X Protein ; metabolism