Cardiac Protective Effects Research Articles

Endogenous κ-Opioid Peptide Mediates the Cardioprotection Induced by Ischemic Postconditioning

The aim of this study was to investigate the underlying mechanism that dynorphin, an endogenous kappa opioid receptor (κ-OR) agonist, triggers antiapoptotic effect of postconditioning (Postcon). In addition to vehicle treatment, Sprague Dawley rats (n = 6) underwent a 30-minute left anterior descending occlusion followed by 2 hours of reperfusion with or without a Postcon stimulus. The selective κ-OR antagonist nor-binaltorphimine (Nor-BNI) was administered intravenously 5 minutes before reperfusion. Infarct size was determined by using 2,3,5-triphenyltetrazolium chloride staining. Blood plasma concentrations of creatine kinase (CK) and lactate dehydrogenase (LDH) and myocardial caspase-3 activity were analyzed spectrophotometrically. Myocardial apoptosis was analyzed by the detection of terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling. Immunoreactive dynorphin in blood serum and myocardium was measured by means of an antigen-competitive enzyme-linked immunosorbent assay. Infarction size, caspase-3 activity, apoptotic index, and CK and LDH levels were significantly higher in the ischemic/reperfusion group than in the vehicle group (P < 0.01). Postcon significantly reduced infarction size, caspase-3 activity, apoptotic index, CK and LDH levels (P < 0.01 vs. ischemic/reperfusion). Dynorphin content significantly increased after Postcon (P < 0.01). All the effects described above were abolished by Nor-BNI, with the exception of dynorphin content. We found that cardiac protection and antiapoptotic effect of Postcon is mediated by the activation of κ-OR. Effect of Postcon is mediated, at least partially, by enhanced dynorphin expression.

EFFECTS OF DEEP-SEA WATER ON CARDIAC ABNORMALITY IN HIGH-CHOLESTEROL DIETARY MICE

ABSTRACT Our recent studies indicated that electrodialysed deep-sea water (ED-DSW) revealed the cardiovascular health effects, such as hindrances of the dietary-induced evaluation of total cholesterol (TC), triglyceride (TG) and nonhigh-density-lipoprotein cholesterol (HDL-C), as well as improvement of HDL-C/non-HDL-C ratio and blood pressure. In the current study, we further revealed the beneficial effects of ED-DSW on high-cholesterol dietary mice by reducing abnormal cardiac architecture, apoptosis and enhancing insulin-like growth factor-1 receptor (IGF-1R) cardiac survival signaling compared with those mice that were treated with distilled water, reverse osmosis (RO)-DSW or 10% (v/v) dilution with ddH2O (10% DSW). These findings further clarified the possible mechanisms of cardiac protective effects of ED-DSW and might suggest ED-DSW as an ingredient of cardiovascular health food in some niche markets. PRACTICAL APPLICATIONS Deep-sea water (DSW) has been applied on several fields including aquaculture, agriculture, food processing, cosmetics and medicine. Recently, we have indicated that high-cholesterol dietary mice drinking electrodialysed DSW (ED-DSW) showed decreased serum lipids, blood pressure and improving blood cholesterol profile. In this study, we further demonstrated the beneficial effects of ED-DSW on high-cholesterol dietary mice by reducing abnormal cardiac architecture, apoptosis in left ventricle and increasing cardiac survival signaling, such as insulin-like growth factor-1 receptor, phosphoinositide-3-kinases and p-AKT/AKT ratio. Altogether, these findings indicated that ED-DSW revealed the cardiac protective effects and might be suggested as an ingredient of cardiovascular health food in a variety of niche markets.

Toll-like Receptor 4 Signaling Confers Cardiac Protection against Ischemic Injury via Inducible Nitric Oxide Synthase- and Soluble Guanylate Cyclase-dependent Mechanisms

Prior administration of a small dose of lipopolysaccharide confers a cardiac protection against ischemia-reperfusion injury. However, the signaling mechanisms that control the protection are incompletely understood. We tested the hypothesis that Toll-like receptor 4 (TLR4) mediates the ability of lipopolysaccharide to protect against cardiac ischemia-reperfusion injury through distinct intracellular pathways involving myeloid differentiation factor 88 (MyD88), TIR-domain-containing adaptor protein-inducing interferon-β-mediated transcription factor (Trif), inducible nitric oxide synthase (iNOS), and soluble guanylate cyclase (sGC). Wild-type mice and genetically modified mice, that is TLR4-deficient (TLR4(-def)), TLR2 knockout (TLR2(-/-)), MyD88(-/-), Trif(-/-), iNOS(-/-), and sGCα1(-/-), were treated with normal saline or 0.1 mg/kg lipopolysaccharide intraperitoneally. Twenty-four hours later, isolated hearts were perfused in a Langendorff apparatus and subsequently subjected to 30 min global ischemia and reperfusion for as long as 60 min. Left ventricular function and myocardial infarction sizes were examined. Compared with saline-treated mice, lipopolysaccharide-treated mice had markedly improved left ventricular developed pressure and dP/dt(max) (P < 0.01) and reduced myocardial infarction sizes (37.2 ± 3.4% vs. 19.8 ± 4.9%, P < 0.01) after ischemia-reperfusion. The cardiac protective effect of lipopolysaccharide was abolished in the TLR4(-def) and MyD88(-/-) mice but remained intact in TLR2(-/-) or Trif(-/-) mice. iNOS(-/-) mice or wild-type mice treated with the iNOS inhibitor 1400W failed to respond to the TLR4-induced nitric oxide production and were not protected by the lipopolysaccharide preconditioning. Although sGCα(1)(-/-) mice had robust nitric oxide production in response to lipopolysaccharide, they were not protected by the TLR4-elicited cardiac protection. TLR4 activation confers a potent cardiac protection against ischemia-reperfusion injury via a MyD88-dependent, but Trif-independent, mechanism. iNOS/sGC are essential for the TLR4-induced cardiac protection.

Salvianolic acid B and Tanshinone IIA attenuate myocardial ischemia injury in mice by NO production through multiple pathways

Salvia miltiorrhiza (Danshen) has been widely used for the treatment of cardiac and cerebrovascular disease throughout history. The objective of this study is to further elucidate the mechanisms underlying Danshen's cardiac protective effects to support its clinical evidence. AND RESULTS: Salvianolic acid B (Sal B) and Tanshinone IIA (Tan IIA) are two of the major components in Danshen. We observed that Sal B and Tan IIA have cardioprotective effects in an in vivo myocardial infarction model of C57 mice, have vasodilator action in a ex vivo micro-artery system through the endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) pathway and are involved in the regulation of the L-arginine/eNOS/NO pathways in human umbilical vein endothelial cells (HUVECs). Both Sal B and Tan IIA inhibited cardiac hypertrophy and infarction sizes and improved cardiac function at 4 weeks after induction of infarction. Furthermore, an eNOS inhibitor (L-NAME) obliterated the observed effects. Sal B and Tan IIA mediated vasodilatation in mice coronaries ex vivo, the effect of which was decreased with either L-NAME or PI3K inhibitor (LY294002). In addition, Sal B and Tan IIA-induced vasodilatation was observed ex vivo in the microvessels of eNOS-/- mice. Sal B and Tan IIA also stimulated eNOS phosphorylation in a concentration- and time-dependent manner in the HUVEC culture, which was diminished by LY294002. In addition, Sal B and Tan IIA were found to stimulate the phosphorylation of AMPK (Thr(172)) and Akt (Ser(473)), while compound C significantly decreased the phosphorylation of Akt (Ser(473)) mediated by both. Finally, Sal B and Tan IIA were found to increase NO production, induce [(3)H]-L-arginine uptake and increase the CAT-1 and CAT-2B mRNA levels in HUVEC culture. These findings suggest that both Sal B and Tan IIA have cardioprotective function in certain levels through multiple targets related with NO production, such as eNOS phosphorylation, L-arginine uptake and CAT expression, which may have major clinical implications.

Myocardial Protective Effect of Human Atrial Natriuretic Peptide in Cardiac Surgery - "hANP Shot" in Clinical Safety Trial -

We studied low-dose human atrial natriuretic peptide (hANP) infusion therapy during cardiac surgery and reported the cardiac and renal protective effects. The efficacy of a bolus injection of hANP (the "hANP shot") simultaneously with induction of cardioplegia has been proven in animal experiments. In the present study the clinical effects of this "hANP shot" were examined. The subjects were 67 patients undergoing Coronary artery bypass grafting. At the time of inducing cardioplegia, 1 group received a simultaneous bolus injection of 100 μg of hANP (hANP group) and the other group received an injection of physiological saline (placebo group). The primary endpoints were (1) operative mortality and complications, and (2) the creatine kinase isoenzyme MB (CPK-MB), troponin-I, and human heart fatty acid binding protein (H-FABP) levels. The secondary endpoints were (1) the incidence of arrhythmia, and levels of (2) atrial and B-type natriuretic peptides, and cyclic guanosine monophosphate (cGMP), and (3) renin, angiotensin II, and aldosterone. Postoperative CPK-MB, troponin-I, and H-FABP levels were significantly lower in the hANP group than in the placebo group. Postoperative arrhythmia was significantly less frequent in the hANP group than in the placebo group. It is possible to achieve cardioprotective effects based on the safety of the "hANP shot", as well as from biomarkers of ischemia and results related to arrhythmia. The "hANP shot" should also be evaluated as a safer and new cardioprotective method for cardiac surgery.

Abstract P5-10-16: Iodine/Anthracyclines Is the Best Combination Against Mammary Cancer. Antineoplastic Synergism and Cardioprotection

Abstract Mammary cancer is the world's most common malignant neoplasia for women. Recently, the mortality for breast cancer has fallen due principally to early detection and to use of neoadjuvant chemotherapy. Anthracycline antibiotics are the most commonly used anticancer drugs, and Doxorubicin (DOX) is the first choice to treat mammary cancer. Nevertheless, its use has limited by its cadiotoxic side effects, which are generated by free radicals. Our studies in methylnitrosourea (MNU)-induced mammary cancer models have shown that supplementation with moderately high doses of molecular iodine (I2) exhibits two distinctive and beneficial effects: antineoplastic and antioxidant. In the present work we explored these dual characteristic of I2 (0.05%) as an adjuvant to DOX16 (therapeutic dose of 16 mg/kg) and DOX8 (8 mg/kg) in female Sprague Dawley rats (200 g) with tumors induced by a single dose of 50 mg MNU per Kg. Iodine intake is initiated 2 days before DOX application and continues up to sacrifice 7 days later. The following parameters were registered: body weight, tumor size, tumor proliferation rate (proliferating cell nuclear antigen, PCNA), serum creatinine kinase-MB activity (CK-MB), cardiac lipoperoxidation (cLPO), and cardiac catalase activity (cCAT). Values correspond to mean± SD. Different superscripts represent significant (p≥0.05). Tumor reduction was greater in the DOX16 + I2 group than in the DOX 16 group (75% vs. 50%, respectively), and was associated with a significantly greater decrease in the rate of tumor cell proliferation (25% vs 10% decrease in PCNA-positive cells), showing the synergistic effect of I2. In contrast, at both DOX doses, the DOX + I2, groups had lower body weight loss and less cardiac damage (CK-MB; 280% vs 100%, cLPO 100% vs 0%) than with DOX alone. cCAT was not changed by any of the treatments.Conclusions: Iodine acts as an adjuvant by significantly enhancing the antiproliferative effect of DOX at a therapeutic dose (DOX16), and it exerts significant general and cardiac protective effects that do not involve catalase activation. Cellular and molecular mechanisms involved in these dual effects of iodine are currently being analyzed. The authors thank Drs. Mauricio Diaz, Marcela Lizano, and Brenda Anguiano as well as Biol. Felipe Ortiz for their technical assistance and Leonor Casanova for academic supports. We also thank Dr. Dorothy Pless for proof-reading. Supported in part by PAPIIT/UNAM 201210 and CONACYT 78955 and 47928/47928. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-16.

E0152 Endogenous κ opioid peptide mediates the cardioprotection induced by ischaemic postconditioning

AimPostconditioning is brief cycles of reperfusion and ischaemia during the early phase of reperfusion following a prolonged ischaemic insult. Opioids are well-known endogenous triggers of preconditioning. Because postconditioning shares the...

E0063 Cardioprotection by ischaemic preconditioning is lost in isolated diabetic hearts: role of transient receptor potential vanilloid 1

ObjectiveExtensive studies demonstrated that diabetes abolished the effectiveness of cardioprotection by ischaemic preconditioning (IPC) during ischaemia/reperfusion. Transient receptor potential vanilloid type 1 (TRPV1) contributes to the cardioprotective effect of IPC...

Role of extracellular signal-regulated kinase in cardioprotective and anti-apoptotic effects of nitric oxide after myocardial ischemia and reperfusion

Objective To determine whether extracellular signal-regulated kinase (ERK) participates in the whole organ or whole animal level in the cardioprotective and anti-apoptotic effects of nitric oxide (NO) during myocardial ischemia/reperfusion (MI/R) injury and the mechanism of ERK and NO in anti-apoptotic effect. Methods Isolated perfused mouse hearts were subjected to 20 min of global ischemi-a and 120 min of reperfusion. During reperfusion period, the hearts were treated with either vehicle or NO donor (SNAP, 10μmol/L). To determine the role of ERK in the anti-apoptotic and cardioprotective effects of NO, some mouse hearts were pre-treated (10 min before ischemia) with U0126, a selective MEK1/2 inhibitor (1μmol/L). Results The group treated with SNAP showed marked myocardial protection effect. Their apoptosis is obviously inhibited (TUNEL and Caspase-3 activity,P <0.01). Their cardiac functional recovery was better (P<0.01). Besides, as compared with vehicle group, treatment with SNAP resulted in a 2. 5-fold increase in ERK activation. Pre-treatment with U0126 slightly increased post-ischemic myocardial apoptosis but showed httle effect on cardiac functional recovery. However, U0126 completely blocked ERK activation induced by SNAP and markedly, although not completely, blocked the cardiac protective effect of SNAP. Conclusion The anti-apoptotic and myocardial protection effect of NO is at least in part, mediated through activation of ERK in ischemic/reperfused heart. Key words: Nitric oxide; ERK; Myocardial ischemia; Reperfusion injure; Apoptosis

Impact of vascular remodeling and of heart rate variability on antihypertensive and cardiovascular effects of indapamide retard in hypertensive patients

Objective. To compare the antihypertensive and cardiovascular protection effects of Indapamide retard in response to arterial remodeling and heart rate variability (HRV) in hypertensive patients. Design and methods. Structural and functional indices of heart and brachial artery (BA) by ultrasound examination, circadian blood pressure (BP) rhythm and HRV by 24-hour ECG and BP monitoring were assessed at baseline and after 6-month therapy with Indapamide retard. Patients were divided into 2 groups: 1st group included 37 patients without arterial remodeling; 2nd group - 48 patients with arterial remodeling. Results. Antihypertensive effect of Indapamide retard did not differ in groups. Changes of HRV indices were signifi cantly higher in 1st group, but the regression of vessel remodeling and increasing of endothelium-dependent vasodilation were signifi cant in 2nd group. Conclusion. This study shows that cardiac protection and antihypertensive effects of Indapamide retard realize through autonomic modulation effect in absence of vascular remodeling, but direct vascular effect is observed in patients with vascular remodeling.

Benidipine, a dihydropyridine L-type/T-type calcium channel blocker, affords additive benefits for prevention of cardiorenal injury in hypertensive rats

Benidipine is a dihydropyridine calcium channel blocker inhibiting not only L-type but also T-type calcium channels. To elucidate potential additive benefit of benidipine for prevention of cardiorenal injury, we compared the cardiac and renal protective effects of equihypotensive doses of benidipine and cilnidipine in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were divided into five groups, and were given vehicle, benidipine at 1 or 3 mg/kg per day, or cilnidipine at 1 or 3 mg/kg per day for 7 weeks, and the protective effects against cardiorenal injury were compared among each group. Benidipine and cilnidipine at the same doses exerted comparable hypotensive effects on SHRSP throughout the treatment. Despite equihypotensive effects between both drugs, benidipine prevented cardiac hypertrophy, fibrosis, and inflammation to a greater extent than cilnidipine. Moreover, benidipine prevented glomerulosclerosis, tubulointerstitial injury, and renal inflammation more than cilnidipine. To elucidate the underlying mechanism of more beneficial effects of benidipine than cilnidipine, we compared the effects of these drugs on cardiac and renal oxidative stress, and aldosterone in SHRSP. Benidipine reduced both cardiac and renal NADPH oxidase activities in SHRSP more than cilnidipine, being associated with more attenuation of cardiac and renal superoxide by benidipine. Furthermore, serum aldosterone was significantly reduced by benidipine but not by cilnidipine. Benidipine exerted more protective effects against cardiorenal injury of hypertensive rats than cilnidipine, through more attenuation of oxidative stress than cilnidipine, and the reduction of aldosterone. Benidipine, via blockade of T-type calcium channels, seems to elicit additive benefits for prevention of hypertensive cardiorenal injury.

AZELNIDIPINE, UNIQUE CALCIUM CHANNEL ANTAGONIST COULD PREVENT STRESS INDUCED CARDIAC DYSFUNCTION LIKE ALPHA AND BETA BLOCKER: PP.1.32

Background and Purpose: We have reported that α and βblocker, such as labetalol, protects against emotional stress-induced cardiac dysfunction but protective effects of other antihypertensive drug, such as calcium antagonist is unknown. Azelnidipine is a unique calcium antagonist which does not increase heart rate. The purpose of this study is to evaluate the effect of azelnidipine to prevent stress induced cardiac dysfunction. Methods: Rats premedicated with azelnidipine (0.3 mg/kg), labetalol (3 mg/kg) or vehicle, were restrained for 30 minutes (immobilization stress: IMO) to reproduce emotional stress, and anesthetized to release stress. We measured the fractional area change (FAC) using SONOS5500 (Philips) with s12 probe (frequency: 5–12 MHz, frame rate: 120 Hz) at the end of IMO and every 10 min for 60 minutes. Results: During IMO, FAC with labetalol was significantly lower than that with azelnidipine or vehicle. At 20 minutes after IMO, FAC with azelnidipine or labetalol was significantly higher than that with vehicle (84±9% vs. 73±5%, 60±7%, p < 0.05). During IMO, BP with azelnidipine or labetalol was significantly lower than that with vehicle (107±5mmHg, 114±4mmHg, vs 126±2mmHg, p < 0.05). During study, HR with labetalol was significantly lower than that with azelnidipine or vehicle. Conclusion: Acute administration of azelnidipine, could prevent a sudden drop of cardiac function after acute stress like IMO. Azelnidipine might have a protective effect on stress induced cardiac dysfunction like α and β blocker.

MG53 Constitutes a Primary Determinant of Cardiac Ischemic Preconditioning

Ischemic heart disease is the greatest cause of death in Western countries. The deleterious effects of cardiac ischemia are ameliorated by ischemic preconditioning (IPC), in which transient ischemia protects against subsequent severe ischemia/reperfusion injury. IPC activates multiple signaling pathways, including the reperfusion injury salvage kinase pathway (mainly PI3K-Akt-glycogen synthase kinase-3beta [GSK3beta] and ERK1/2) and the survivor activating factor enhancement pathway involving activation of the JAK-STAT3 axis. Nevertheless, the fundamental mechanism underlying IPC is poorly understood. In the present study, we define MG53, a muscle-specific TRIM-family protein, as a crucial component of cardiac IPC machinery. Ischemia/reperfusion or hypoxia/oxidative stress applied to perfused mouse hearts or neonatal rat cardiomyocytes, respectively, causes downregulation of MG53, and IPC can prevent ischemia/reperfusion-induced decrease in MG53 expression. MG53 deficiency increases myocardial vulnerability to ischemia/reperfusion injury and abolishes IPC protection. Overexpression of MG53 attenuates whereas knockdown of MG53 enhances hypoxia- and H(2)O(2)-induced cardiomyocyte death. The cardiac protective effects of MG53 are attributable to MG53-dependent interaction of caveolin-3 with phosphatidylinositol 3 kinase and subsequent activation of the reperfusion injury salvage kinase pathway without altering the survivor activating factor enhancement pathway. These results establish MG53 as a primary component of the cardiac IPC response, thus identifying a potentially important novel therapeutic target for the treatment of ischemic heart disease.

Compound K produces cardiac protection by activating Akt phosphorylation

Ginseng root is one of the most popular herbs throughout the world and it has been used as a medicine to enhance stamina and capacity to cope with fatigue and physical stress. In this study, we focused the cardiac protective effects of Compound K (C‐K; 20‐O‐D‐glucopyranosyl‐20(S)‐protopanaxadiol), which is a protopanaxadiol metabolite derived from ginsenoside Rb1, Rb2, and Rc by the metabolic actions of intestinal bacteria.Mice were exposed to 30 min ischemia followed by 120 min of reperfusion (control). Some mice were assigned to C‐K, or PI3K inhibitor, wortmannin. C‐K preconditioned significantly reduced infarct size compared to control group (22.4 ± 2.5% [n = 7] vs. 43.2 ± 2.0% [n = 12] respectively, p&lt;0.05) and wortmannin eliminated the protection produced by C‐K (43.3 ± 2.4% [n = 7]). Additionally, the hearts treated with C‐K had a 2‐fold increase in basal phosphorylation of Akt and pretreated with wortmannin completely abolished Akt phosphorylation in response to C‐K treatment.These results reveal that C‐K produces cardiac protection in mice in association with PI3K/Akt signaling.

Amelioration of myocardial ischemia/reperfusion injury by leptin pretreatment and ischemic preconditioning in mouse

To study the effects and role of leptin pretreatment and ischemic preconditioning (IPC) on the reduction of myocardial ischemia/reperfusion injury (MIRI) in mouse. Thirty-six male C57BL/6 mice were randomized into five groups: (1)sham operation group (n=12); (2) brief ischemia/reperfusion (I/R) treatment group (n=6), in which the mice were subjected to three cycles of a 3-minute regional ischemia followed by a 5-minute reperfusion (I/R cycle); (3) MIRI group (n=6), in which MIRI was established in the mice by blocking anterior descending branch of left coronary artery for 30 minutes, followed by 120 minutes reperfusion; (4) IPC group (n=6), in which three I/R cycles were performed on the mice followed by the MIRI protocol; (5) leptin pretreatment group (leptin group, n=6), in which 50 microg/kg of leptin was injected intraperitoneally to the mice 30 minutes before myocardial ischemia. From 6 mice of the sham operation group and from the mice of brief I/R group, serum samples were collected at different time points (0, 5, 30 and 120 minutes) after reperfusion to measure changes in serum leptin level. From the rest of the mice, blood and heart samples were harvested at 120 minutes after reperfusion to analyze the myocardial function and infarct size, leptin, myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) levels. IPC procedure resulted in an increase in serum leptin level shortly after reperfusion. The leptin level increased significantly than that of sham operation group [(6.24+/-2.34) microg/L vs. (1.35+/-0.45) microg/L] at 5 minutes after I/R, and reached the peak value of (12.36+/-1.33) microg/L at 30 minutes after I/R. Then it gradually decreased to its original (0 minute after reperfusion) value [(1.96+/-1.33) microg/L] at 120 minutes after I/R. There was no difference compared with sham operation group [(1.16+/-0.25) microg/L, P>0.05]. Administration of leptin or IPC before MIRI significantly reduced infarct size [(11.50+/-2.26)%, (9.00+/-1.90)% vs. (37.00+/-2.53)%], the myocardial leptin levels [(8.36+/-3.42) microg/g, (6.71+/-2.03) microg/g vs. (15.51+/-3.92) microg/g], MPO [(17.10+/-3.95) microg/g, (13.33+/-2.88) microg/g vs. (30.83+/-4.06) microg/g], serum leptin levels [(15.03+/-1.87) microg/L, (11.85+/-0.72) microg/L vs. (29.55+/-2.31) microg/L], serum TNF-alpha [(35.10+/-10.12) ng/L, (27.04+/-5.18) ng/L vs. (81.34+/-14.20) ng/L], and IL-6 levels [(167.39+/-72.83) ng/L, (149.13+/-37.69) ng/L vs. (477.30+/-29.09) ng/L, all P<0.01]. Pretreatment using leptin results in preconditioning-like tolerance against infarction dysfunction. This cardiac protection effect is mediated, in part, via suppression of inflammation in preconditioned myocardium.

Chronic intermittent hypobaric hypoxia decreases β-adrenoceptor activity in right ventricular papillary muscle

Chronic intermittent hypobaric hypoxia (CIHH) has an effective cardiac protection against ischemia-reperfusion injury. However, the underlying mechanisms are not fully known. It has been shown that blockade of beta-adrenergic receptor exerts anti-arrhythmic action and improves cardiac remodeling in ischemic myocardium. Thus we determined the influence of CIHH on beta-adrenergic receptor activity in right ventricular papillary muscle of rats. We found that the action potential duration in right ventricular papillary muscle was significantly longer in CIHH rats than in control rats. Activation of beta-adrenergic receptor with dl-isoproterenol dose-dependently increased action potential duration and the contractility in right ventricular papillary muscle. In CIHH rats, the prolonged effect of dl-isoproterenol on action potential duration and the positive inotropic effect were significantly decreased compared with that in control rats. Furthermore, radioligand-binding experiments revealed that the density and affinity of beta-adrenergic receptor in right ventricular myocardium was significantly lower in CIHH rats. In addition, Western blot analysis revealed that the membrane-bound G protein G(s)alpha expression level in cardiac myocardium was significantly lower in CIHH rats than that in control rats. Collectively, these data suggest that CIHH suppresses beta-adrenergic receptor action in right ventricular papillary muscle through decreasing receptor density and affinity, as well as membrane-bound G(s)alpha. This mechanism may be involved in the cardiac protective effect of CIHH.

Bioactive Compounds Isolated from Salvia miltiorrhiza Exert Anti-hypertrophic Anti-fibrotic and Cardiac Protective Effects Via Reactive Oxygen Species Pathway

Bioactive Compounds Isolated from Salvia miltiorrhiza Exert Anti-hypertrophic Anti-fibrotic and Cardiac Protective Effects Via Reactive Oxygen Species Pathway

Retrospective analysis of thrombolysis therapy for 64 cases of acute myocardial infarction with elevated ST segment

To explore the cardiac protective effect of integrative therapy in acute myocardial infarction (AMI) with elevated ST segment after reperfusion. Sixty-four AMI patients who having received decimalization by thrombolysis were assigned to two groups by retrospective analysis, 36 patients in the treated group and 28 in the control group. Both were treated by intravenous administering of urokinase for thrombolysis, and to the treated group, intravenous dripping of Xueshuantong Injection (, XST) was added. Serum levels of myocardial associated enzymes were monitored before treatment and at various time points after thrombolysis, and the heart function parameters were detected with color echocardiography before treatment and on the 7th and 14th day of treatment. The patients were followed up for 6 months to observe the incidence of cardiac events. The differences between groups at the peak and peak appearing time of creatine kinase and creatine kinase isoenzyme were not significant. All the heart function parameters on the 7th and 14th day in the treated group were improved and superior to those at the corresponding time points in the control group (P<0.05, P<0.01). Incidence of some heart events in the treated group within the 6-month follow-up period was lesser than that in the control group (P<0.05). XST Injection could provide effective protection for the heart after reperfusion.

Anti-inflammatory and anti-coagulatory activities of caffeic acid and ellagic acid in cardiac tissue of diabetic mice

BackgroundCaffeic acid (CA) and ellagic acid (EA) are phenolic acids naturally occurring in many plant foods. Cardiac protective effects of these compounds against dyslipidemia, hypercoagulability, oxidative stress and inflammation in diabetic mice were examined.MethodsDiabetic mice were divided into three groups (15 mice per group): diabetic mice with normal diet, 2% CA treatment, or 2% EA treatment. One group of non-diabetic mice with normal diet was used for comparison. After 12 weeks supplement, mice were sacrificed, and the variation of biomarkers for hypercoagulability, oxidative stress and inflammation in cardiac tissue of diabetic mice were measured.ResultsThe intake of CA or EA significantly increased cardiac content of these compounds, alleviated body weight loss, elevated plasma insulin and decreased plasma glucose levels in diabetic mice (p < 0.05). These treatments also significantly enhanced plasma antithrombin-III and protein C activities (p < 0.05); and decreased triglyceride content in cardiac tissue and plasma (p < 0.05), in which the hypolipidemic effects of EA were significantly greater than that of CA (p < 0.05). CA or EA significantly lowered cardiac levels of malondialdehyde, reactive oxygen species, interleukin (IL)-beta, IL-6, tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1 (p < 0.05); and retained cardiac activity of glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (p < 0.05). These compounds also significantly up-regulated cardiac mRNA expression of GPX1, SOD and catalase; and down-regulated IL-1beta, IL-6, TNF-alpha and MCP-1 mRNA expression in diabetic mice (p < 0.05).ConclusionThese results support that CA and EA could provide triglyceride-lowering, anti-coagulatory, anti-oxidative, and anti-inflammatory protection in cardiac tissue of diabetic mice. Thus, the supplement of these agents might be helpful for the prevention or attenuation of diabetic cardiomyopathy.

Improvement of heart function in postinfarct heart failure swine models after hepatocyte growth factor gene transfer: comparison of low-, medium- and high-dose groups

Despite advances in surgical and reperfusion therapy, there is no effective therapy currently exists to prevent the progressive decline in cardiac function following myocardial infarction. Hepatocyte growth factor has potent angiogenic and anti-apoptotic activities. The aim of this study was to investigate the therapeutic effect and dose-effect relationship on postinfarction heart failure with different doses of adenovirus-mediated human hepatocyte growth factor (Ad(5)-HGF) transference in swine models. Totally twenty swine were randomly divided into four groups: (a) control group (null- Ad(5), 1 ml); (b) low-dose group (1 x 10(9) Pfu/ml Ad(5)-HGF, 1 ml); (c) medium-dose group (5 x 10(9) Pfu/ml Ad(5)-HGF, 1 ml); (d) high-dose group (1 x 10(10) Pfu/ml Ad(5)-HGF, 1 ml). Four weeks after left anterior descending coronary artery (LAD) ligation, different doses of Ad(5)-HGF were transferred in three therapeutic groups via right coronary artery. Four and seven weeks after LAD ligation, gate cardiac perfusion imaging was performed to evaluate cardiac perfusion and left ventricular ejection fraction (LVEF). Seven weeks after surgery, the apoptotic index of cardiocyte was observed by TUNEL, the expression of Bcl-2, Bax, alpha-SMA and Factor VIII in the border zones were evaluated by immunohistochemistry, respectively. Four weeks after myocardial infarction, no significant difference was observed among four groups. Three weeks after Ad(5)-HGF transfer, the improvement of cardiac perfusion and LVEF was obviously observed, especially after 1 x 10(10) Pfu Ad(5)-HGF transfer. TUNEL assay showed that 5 x 10(9) Pfu and 1 x 10(10) Pfu Ad(5)-HGF treatment had a obvious reduction in the apoptotic index compared with the null-Ad(5) group, especially after 1 x 10(10) Pfu Ad(5)-HGF treatment. The expression of Bcl-2 protein was increased and the expression of Bax protein was inhibited in the 5 x 10(9) Pfu and 1 x 10(10) Pfu Ad(5)-HGF groups compared with the null-Ad(5) group. The vessel density of Factor VIII(+) and alpha-SMA(+) was increased in Ad(5)-HGF groups compared with the null-Ad(5) group. There were no significant differences in angiogenesis, reducing apoptosis and ameliorating heart function between the 1 x 10(9) Pfu Ad(5)-HGF group and the null-Ad(5) group. Although no statistical difference was observed between 1 x 10(10) Pfu and 5 x 10(9) Pfu Ad(5)-HGF groups, the cardiac protective effects of 1 x 10(10) Pfu Ad(5)-HGF treatment were greater than 5 x 10(9) Pfu Ad(5)-HGF treatment. Different doses of Ad5-HGF injected via noninfarct-related artery could induce angiogenesis, reduce apoptosis and ameliorate heart function, and the cardiac protective effects of 1 x 10(10) Pfu Ad5-HGF is of most significance.