Abstract 1588: Midkine Gene Transfer Ameliorates Ischemic Cardiomyopathy through Enhancements of Neovascularization via Akt/PI3 Kinase and ERK Pathways and Anti-Apoptosis by Regulating Bcl-2 and Bax

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Arihiro Sumida ◽  
Mitsuru Horiba ◽  
Hisaaki Ishiguro ◽  
Hiroharu Takenaka ◽  
Norihiro Ueda ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Ventricular Remodeling ◽  
Ischemia Reperfusion ◽  
Fold Increase ◽  
Wistar Rat ◽  
Capillary Density ◽  
Heparin Binding ◽  
Intramyocardial Injection ◽  
Beneficial Effects ◽  
Erk Phosphorylation

Midkine (MK) is a heparin-binding growth factor involved in diverse biological phenomena, e.g. neural survival, carcinogenesis and tissue repair. We have demonstrated recently that MK ameliorates acute myocardial injury by ischemia/reperfusion through prevention of apoptotic reactions. Chronic effects of MK on the ventricular remodeling after myocardial infarction (MI) remain to be confirmed. MI was created in Wistar rat by ligation of the left anterior discending coronary artery. Rats of MK overexpression were prepared by intramyocardial injection of adenoviruses encoding MK (AdMK, n=12) at the onset of MI. Control rats were injected with adenoviruses encoding beta-galactosidase (AdLacZ, n=12). In echocardiography 4w after MI, AdMK showed smaller LVESD and LVEDD than AdLacZ (LVESD: 6.7±0.7 vs. 9.3±0.7mm, LVEDD: 8.7±0.7 vs. 10.7±0.7mm, p<0.01). AdMK had better FS than AdLacZ (FS: 23.0±2.8 vs. 12.4±2.1%, p<0.01). Better preservation of systolic/diastolic function in AdMK than AdLacZ was also recognized in the LV catheterization 6w after MI (dP/dt max : 3092±619 vs. 2171±763mmHg/s, dP/dt min : −2525±878 vs. −1700±722mmHg/s, LVEDP: 3.3±0.9 vs. 8.3±2.2mmHg, p<0.01). Morphological study on AdMK 6w after MI revealed less fibrosis (collagen deposition area: 10.2±5.3 vs. 15.3±4.5%, p<0.05) and a higher vWF-positive capillary density in the perinfarct zone (32±11 vs. 21±5/mm 2 , p<0.01) compared with AdLacZ. In Western blotting, the levels of Akt and ERK phosphorylation and PI3K were elevated in AdMK compared with AdLacZ (pAkt; 2.08-fold increase, pERK; 1.43-fold increase, PI3K; 2.36-fold increase, relative to AdLacZ, p<0.05). In addition, the level of Bcl-2 increased and the level of Bax decreased in AdMK compared with AdLacZ (Bcl-2; 2.15-fold increase, Bax; 3.63-fold decrease, relative to AdLacZ, p<0.01). Overexpression of MK has long-term beneficial effects to reduce the progression of LV remodeling and dysfunction after MI. This amelioration is attributable in part to an enhancement of neovascularization via PI3K/Akt and ERK pathways, and in part to anti-apoptotic actions regulating Bcl-2 and Bax. MK gene transfer might be a new therapeutic strategy for treatment of ischemic heart disease.

scholarly journals Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

2014 ◽  
Vol 222 (2) ◽  
pp. 289-299 ◽  
Author(s):  
Takuya Yoshino ◽  
Tomohisa Nagoshi ◽  
Ryuko Anzawa ◽  
Yusuke Kashiwagi ◽  
Keiichi Ito ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Diastolic Pressure ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Wistar Rat ◽  
Left Ventricular ◽  
Ventricular Contractility ◽  
Independent Manner ◽  
Beneficial Effects ◽  
Physiological Dose

Although persistent excessive actions of aldosterone have unfavorable effects on the cardiovascular system, primarily via mineralocorticoid receptor (MR)-dependent pathways, the pathophysiological significance of aldosterone cascade activation in heart diseases has not yet been fully clarified. We herein examined the effects of short-term aldosterone stimulation at a physiological dose on cardiac function during ischemia–reperfusion injury (IRI). In order to study the effects of aldosterone preconditioning, male Wistar rat Langendorff hearts were perfused with 10−9 mol/l of aldosterone for 10 min before ischemia, and the response to IRI was assessed. Although aldosterone did not affect the baseline hemodynamic parameters, preconditioning actions of aldosterone significantly improved the recovery in left ventricular contractility and left ventricular end-diastolic pressure associated with a reduced activity of creatine phosphokinase released into the perfusate after ischemia–reperfusion. Notably, the MR inhibitor eplerenone did not abrogate these beneficial effects. Biochemical analyses revealed that p38MAPK phosphorylation was significantly increased during aldosterone preconditioning before ischemia, whereas its phosphorylation was substantially attenuated during sustained ischemia–reperfusion, compared with the results for in the non-preconditioned control hearts. This dual regulation of p38MAPK was not affected by eplerenone. The phosphorylation levels of other MAPKs were not altered by aldosterone preconditioning. In conclusion, the temporal induction of the aldosterone cascade, at a physiological dose, has favorable effects on cardiac functional recovery and injury following ischemia–reperfusion in a MR-independent manner. Phasic dynamism of p38MAPK activation may play a key role in the physiological compensatory pathway of aldosterone under severe cardiac pathological conditions.

scholarly journals AMPK is associated with the beneficial effects of antidiabetic agents on cardiovascular diseases

2019 ◽  
Vol 39 (2) ◽  
Author(s):  
Qingguo Lu ◽  
Xuan Li ◽  
Jia Liu ◽  
Xiaodong Sun ◽  
Thomas Rousselle ◽  
...  
Keyword(s):  
Ventricular Remodeling ◽  
Ischemia Reperfusion ◽  
Antidiabetic Agents ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Glucosidase Inhibitors ◽  
Sodium Glucose Cotransporter ◽  
Promising Target ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Cell Energy

Abstract Diabetics have higher morbidity and mortality in cardiovascular disease (CVD). A variety of antidiabetic agents are available for clinical choice. Cardiovascular (CV) safety assessment of these agents is crucial in addition to hypoglycemic effect before clinical prescription. Adenosine 5′-monophosphate-activated protein kinase (AMPK) is an important cell energy sensor, which plays an important role in regulating myocardial energy metabolism, reducing ischemia and ischemia/reperfusion (I/R) injury, improving heart failure (HF) and ventricular remodeling, ameliorating vascular endothelial dysfunction, antichronic inflammation, anti-apoptosis, and regulating autophagy. In this review, we summarized the effects of antidiabetic agents to CVD according to basic and clinical research evidence and put emphasis on whether these agents can play roles in CV system through AMPK-dependent signaling pathways. Metformin has displayed definite CV benefits related to AMPK. Sodium-glucose cotransporter 2 inhibitors also demonstrate sufficient clinical evidence for CV protection, but the mechanisms need further exploration. Glucagon-likepeptide1 analogs, dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors and thiazolidinediones also show some AMPK-dependent CV benefits. Sulfonylureas and meglitinides may be unfavorable to CV system. AMPK is becoming a promising target for the treatment of diabetes, metabolic syndrome and CVD. But there are still some questions to be answered.

scholarly journals Xenon and Isoflurane Reduce Left Ventricular Remodeling after Myocardial Infarction in the Rat

2013 ◽  
Vol 118 (6) ◽  
pp. 1385-1394 ◽  
Author(s):  
Anna B. Roehl ◽  
Sandra Funcke ◽  
Michael M. Becker ◽  
Andreas Goetzenich ◽  
Christian Bleilevens ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Troponin I ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Ischemia Reperfusion ◽  
Capillary Density ◽  
Left Ventricular ◽  
Acute Injury ◽  
Perioperative Myocardial Infarction

Abstract Background: Xenon and isoflurane are known to have cardioprotective properties. We tested the hypothesis that these anesthetics positively influence myocardial remodeling 28 days after experimental perioperative myocardial infarction and compared their effects. Methods: A total of 60 male Sprague–Dawley rats were subjected to 60min of coronary artery occlusion and 120min of reperfusion. Prior to ischemia, the animals were randomized for the different narcotic regimes (0.6 vol% isoflurane, 70 vol% xenon, or intraperitoneal injection of s-ketamine). Acute injury was quantified by echocardiography and troponin I. After 4 weeks, left ventricular function was assessed by conductance catheter to quantify hemodynamic compromise. Cardiac remodeling was characterized by quantification of dilatation, hypertrophy, fibrosis, capillary density, apoptosis, and expression of fetal genes (α/β myosin heavy chains, α-skeletal actin, periostin, and sarco/endoplasmic reticulum Ca2+-ATPase). Results: Whereas xenon and isoflurane impeded the acute effects of ischemia-reperfusion on hemodynamics and myocardial injury at a comparable level, differences were found after 4 weeks. Xenon in contrast to isoflurane or ketamine anesthetized animals demonstrated a lower remodeling index (0.7±0.1 vs. 0.9±0.3 and 1.0±0.3g/ml), better ejection fraction (62±9 vs. 49±7 and 35±6%), and reduced expression of β-myosin heavy chain and periostin. The effects on hypertrophy, fibrosis, capillary density, and apoptosis were comparable. Conclusions: Compared to isoflurane and s-ketamine, xenon limited progressive adverse cardiac remodeling and contractile dysfunction 28 days after perioperative myocardial infarction.

Abstract P298: Finerenone Protects Against the Acute and Chronic Consequences of Renal Ischemia/reperfusion Injury

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Jonatan Barrera-Chimal ◽  
Alan Le Mercier ◽  
Soumaya El-Moghrabi ◽  
Peter Kolkhof ◽  
Frederic Jaisser
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Left Kidney ◽  
Kidney Injury ◽  
Fold Increase ◽  
Renal Ischemia ◽  
Mrna Levels ◽  
Beneficial Effects ◽  
The Right

Introduction: One of the most common causes of acute kidney injury (AKI) is renal ischemia/reperfusion (IR). Mineralocorticoid receptor (MR) antagonism has shown beneficial effects against renal IR consequences. The potential benefit of novel non-steroidal MR antagonists such as finerenone has not been explored. Objective: Evaluate the efficacy of finerenone to prevent the acute and chronic consequences of ischemic AKI. Methods: For the acute study (24 hours), 18 rats were divided in: sham, rats subjected to bilateral renal ischemia of 25 min and rats that received three doses of finerenone at -48 h, -24 h and -1 h before the ischemia. For the chronic study (4 months), 21 rats were divided in: sham, rats with 45 min of bilateral ischemia and rats treated with Finerenone at day -2, -1 and 1h before IR. The left kidney was used for histology and the right kidney for molecular analysis. Results: After 24 h of reperfusion, the untreated IR rats presented a 3-fold increase in plasma creatinine, accompanied by 40% of tubules presenting cell detachment and casts. Kim-1 and NGAL mRNA levels were induced by 30-fold. In contrast, the rats that received finerenone presented normal creatinine and significantly fewer injured tubules (11%) and a less pronounced induction of kim-1 and NGAL (8-fold). After 4 months, the untreated IR rats developed chronic kidney disease (CKD), evidenced by kidney dysfunction, increased proteinuria (121.6 vs. 14.3 mg/24h in sham) and renal vascular resistance (16.8 vs. 11.4 mmHg/mL in sham). Tubular dilation, extensive tubule-interstitial fibrosis and an increase in kidney TGF-β and Collagen-I mRNA levels also characterized CKD. The transition from AKI to CKD was fully prevented by finerenone administration at the time of IR. Conclusion: Altogether, our data shows that finerenone is able to prevent AKI induced by IR as well as the chronic and progressive deterioration of kidney function and structure.

Pharmacokinetics of Full Length and Two-Domain Tissue Factor Pathway Inhibitor in Combination with Heparin in Rabbits

1993 ◽  
Vol 70 (03) ◽  
pp. 454-457 ◽  
Author(s):  
Claus Bregengaard ◽  
Ole Nordfang ◽  
Per Østergaard ◽  
Jens G L Petersen ◽  
Giorgio Meyn ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Anticoagulant Activity ◽  
Fold Increase ◽  
Volume Of Distribution ◽  
Full Length ◽  
Heparin Binding ◽  
Extrinsic Pathway ◽  
C Terminus ◽  
Tissue Factor Pathway

SummaryTissue factor pathway inhibitor (TFPI) is a feed back inhibitor of the initial activation of the extrinsic pathway of coagulation. In humans, injection of heparin results in a 2-6 fold increase in plasma TFPI and recent studies suggest that TFPI may be important for the anticoagulant activity of heparin. Full length (FL) TFPI, but not recombinant two-domain (2D) TFPI, has a poly cationic C-terminus showing very strong heparin binding. Therefore, we have investigated if heparin affects the pharmacokinetics of TFPI with and without this C-terminus.FL-TFPI (608 U/kg) and 2D-TFPI (337 U/kg) were injected intravenously in rabbits with and without simultaneous intravenous injections of low molecular weight heparin (450 anti-XaU/kg).Heparin decreased the volume of distribution and the clearance of FL-TFPI by a factor 10-15, whereas the pharmacokinetics of 2D-TFPI were unaffected by heparin. When heparin was administered 2 h following TFPI the recovery of FL-TFPI was similar to that found in the group receiving the two compounds simultaneously, suggesting that the releasable pool of FL-TFPI is removed very slowly in the absence of circulating heparin.

Role of Heart Rate Reduction in the Management of Myocarditis

2018 ◽  
Vol 24 (3) ◽  
pp. 365-378 ◽  
Author(s):  
Chen Guang-Yi ◽  
Ge Li-Sha ◽  
Li Yue-Chun
Keyword(s):  
Heart Rate ◽  
Nitrosative Stress ◽  
Ventricular Remodeling ◽  
Animal Experiments ◽  
Viral Myocarditis ◽  
Protective Effects ◽  
Heart Rate Reduction ◽  
Rate Reduction ◽  
Beneficial Effects ◽  
Biological Technique

The morbidity of myocarditis demonstrates an upward tendency by years, is commonly defined as the inflammation of myocytes and is caused by multiple factors. With the development of the molecular biological technique, great breakthroughs in the diagnosis and understanding of pathophysiological mechanisms of myocarditis have recently been achieved. Several questions remain unresolved, however, including standard treatment approaches to myocarditis, which remain controversial and ambiguous. Heart rate, as an independent risk factor, has been shown to be related to cardiac disease. Recent studies also show that the autonomic nervous system is involved in immunomodulatory myocarditis processes. Heart rate reduction treatment is recommended in myocarditis based on a number of animal experiments and clinical trials. It is possible that heart rate-lowering treatments can help to attenuate the inflammatory response and myocyte injury and reverse ventricular remodeling. However, how to execute the protective effects of heart rate reduction on myocarditis is still not clear. In this review, we discuss the pathogenesis and pathophysiological process of viral myocarditis and propose heart rate lowering as a therapeutic target for myocarditis, especially in light of the third-generation β-blockade carvedilol and funny channel blocker ivabradine. We also highlight some additional beneficial effects of such heart rate reduction agents, including anti-inflammatory, antioxidation, anti-nitrosative stress, anti-fibrosis and antiapoptosis properties.

Beneficial effects of natural compounds on experimental liver ischemia-reperfusion injury

2021 ◽  
Author(s):  
Camila Dossi ◽  
Romina Vargas ◽  
Rodrigo Valenzuela ◽  
Luis Videla
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Natural Compounds ◽  
Liver Ischemia ◽  
Hepatic Surgery ◽  
Beneficial Effects ◽  
Underlying Mechanisms ◽  
Experimental Liver

Liver ischemia-reperfusion injury (IRI) is a phenomenon inherent to hepatic surgery that severely compromises the organ functionality, whose underlying mechanisms involve cellular and molecular interrelated processes leading to the development...

scholarly journals Myocardial fibrosis reversion via rhACE2-electrospun fibrous patch for ventricular remodeling prevention

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Zeping Qiu ◽  
Jingwen Zhao ◽  
Fanyi Huang ◽  
Luhan Bao ◽  
Yanjia Chen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Fibrosis ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Cost Effective ◽  
Intramyocardial Injection ◽  
Undesirable Consequence ◽  
Adverse Remodeling

AbstractMyocardial fibrosis and ventricular remodeling were the key pathology factors causing undesirable consequence after myocardial infarction. However, an efficient therapeutic method remains unclear, partly due to difficulty in continuously preventing neurohormonal overactivation and potential disadvantages of cell therapy for clinical practice. In this study, a rhACE2-electrospun fibrous patch with sustained releasing of rhACE2 to shape an induction transformation niche in situ was introduced, through micro-sol electrospinning technologies. A durable releasing pattern of rhACE2 encapsulated in hyaluronic acid (HA)—poly(L-lactic acid) (PLLA) core-shell structure was observed. By multiple in vitro studies, the rhACE2 patch demonstrated effectiveness in reducing cardiomyocytes apoptosis under hypoxia stress and inhibiting cardiac fibroblasts proliferation, which gave evidence for its in vivo efficacy. For striking mice myocardial infarction experiments, a successful prevention of adverse ventricular remodeling has been demonstrated, reflecting by improved ejection fraction, normal ventricle structure and less fibrosis. The rhACE2 patch niche showed clear superiority in long term function and structure preservation after ischemia compared with intramyocardial injection. Thus, the micro-sol electrospun rhACE2 fibrous patch niche was proved to be efficient, cost-effective and easy-to-use in preventing ventricular adverse remodeling.

scholarly journals Reducing Cardiac Injury during ST-Elevation Myocardial Infarction: A Reasoned Approach to a Multitarget Therapeutic Strategy

2021 ◽  
Vol 10 (13) ◽  
pp. 2968
Author(s):  
Alessandro Bellis ◽  
Giuseppe Di Gioia ◽  
Ciro Mauro ◽  
Costantino Mancusi ◽  
Emanuele Barbato ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Reperfusion Injury ◽  
Therapeutic Strategy ◽  
Ventricular Remodeling ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
St Elevation Myocardial Infarction ◽  
Ischemic Time ◽  
St Elevation

The significant reduction in ‘ischemic time’ through capillary diffusion of primary percutaneous intervention (pPCI) has rendered myocardial-ischemia reperfusion injury (MIRI) prevention a major issue in order to improve the prognosis of ST elevation myocardial infarction (STEMI) patients. In fact, while the ischemic damage increases with the severity and the duration of blood flow reduction, reperfusion injury reaches its maximum with a moderate amount of ischemic injury. MIRI leads to the development of post-STEMI left ventricular remodeling (post-STEMI LVR), thereby increasing the risk of arrhythmias and heart failure. Single pharmacological and mechanical interventions have shown some benefits, but have not satisfactorily reduced mortality. Therefore, a multitarget therapeutic strategy is needed, but no univocal indications have come from the clinical trials performed so far. On the basis of the results of the consistent clinical studies analyzed in this review, we try to design a randomized clinical trial aimed at evaluating the effects of a reasoned multitarget therapeutic strategy on the prevention of post-STEMI LVR. In fact, we believe that the correct timing of pharmacological and mechanical intervention application, according to their specific ability to interfere with survival pathways, may significantly reduce the incidence of post-STEMI LVR and thus improve patient prognosis.

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