P2563Effects of rivaroxaban on cardiac remodeling after experimental myocardial infarction in mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
N Nakanishi ◽  
K Kaikita ◽  
M Ishii ◽  
Y Oimatsu ◽  
T Mitsuse ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Mrna Expression ◽  
Cardiac Remodeling ◽  
Transforming Growth Factor ◽  
Vehicle Group ◽  
Chow Diet ◽  
Pathological Analysis ◽  
Infarcted Area ◽  
Tnf Α

Abstract Background Rivaroxaban, a direct activated factor X (FXa) inhibitor, has been established for prevention and treatment of arterial and venous thrombosis. Although FXa plays an important role in thrombosis, FXa also involves in inflammation via the protease-activated receptor (PAR)-1 and PAR-2 pathway. We assessed the hypothesis that rivaroxaban might protect cardiac remodeling after myocardial infarction (MI) in mice. Methods MI was induced in wild-type mice by permanent ligation of the left anterior descending coronary artery. At 1 day after MI, mice were randomly assigned to the rivaroxaban and vehicle groups. In the rivaroxaban group, the mice were provided with regular chow diet including rivaroxaban (2400ppm) after the randomization. We evaluated the cardiac function by echocardiography, expression of mRNA and protein in the infarcted and non-infarcted area 7 days after MI. Furthermore, we measured infarct size, infiltration of inflammatory cells by pathological analysis 7 days after MI. Results The fractional shortening (%FS) and Interventricular Septal thickness in diastole (IVSTd) was significantly improved 7 days after MI in the rivaroxaban group compared with the vehicle group (%FS, p=0.01; IVSTd, p=0.013). As for pathological analysis, rivaroxaban decreased infarct size (p=0.026) and the number of infiltrated macrophages in the non-infarcted area (p=0.011) compared with vehicle. The mRNA expression in tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β in the infarcted area and atrial natriuretic peptide (ANP) in the non-infarcted area was significantly lower in the rivaroxaban group compared with the vehicle (TNF-α, p=0.015; TGF-β, p=0.019; ANP, p=0.012). PAR-1 and PAR-2 mRNA expression in the infarcted area significantly decreased 7 days after MI in the rivaroxaban group compared with the vehicle (PAR-1, p=0.005; PAR-2, p=0.037). Furthermore, western blot analysis demonstrated that the phosphorylation of Extracellular Signal-regulated Kinase (ERK) and c-Jun N-terminal Kinase (JNK) in the non-infarcted area significantly decreased 7 days after MI in the rivaroxaban group compared with the vehicle (ERK, p=0.015; JNK, p=0.002). Conclusions The present study showed that rivaroxaban protected against cardiac dysfunction, probably due to the suppression of PAR-mediated increase of pro-inflammatory cytokines post-MI. Rivaroxaban might be potentially effective for improving the cardiac remodeling after MI. Acknowledgement/Funding This study was supported in part by trust-research grant from Bayer Yakuhin, Ltd.

scholarly journals Cardioprotective effects of Ginsenoside compound-Mc1 and Dendrobium Nobile Lindl against myocardial infarction in an aged rat model: Involvement of TLR4/NF-κB signaling pathway

2021 ◽  
Vol 19 ◽  
pp. 205873922110005
Author(s):  
Yongle Sun ◽  
Jing Geng ◽  
Deyu Wang
Keyword(s):  
Myocardial Infarction ◽  
Combination Therapy ◽  
Infarct Size ◽  
Signaling Pathway ◽  
Left Ventricular ◽  
Male Rats ◽  
Dendrobium Nobile ◽  
Tnf Α ◽  
Cardioprotective Effects ◽  
Dendrobium Nobile Lindl

Aging is the crucial co-morbidity that prevents the full cardioprotection against myocardial ischemia/reperfusion (I/R) injury. Combination therapy as a promising strategy may overcome this clinical problem. This study aimed to investigate the cardioprotective effects of Ginsenoside compound-Mc1 (GMc1) and Dendrobium Nobile Lindl (DNL) in myocardial I/R injury and explore the involvement of the TLR4/NF-κB signaling pathway in aged rats. In vivo I/R injury and myocardial infarction was established by temporary coronary ligation in 22–24 months’ old Sprague Dawley male rats. GMc1 (10 mg/kg) and DNL (80 mg/kg) were administered intraperitoneally for 4 weeks and orally for 14 days, respectively, before I/R injury. Infarct size was measured through triphenyl-tetrazolium-chloride staining. ELISA assay was conducted to quantify the levels of cardiotroponin, and myocardial content of TNF-α and glutathione. Western blotting was employed to detect the expression of TLR4/MyD88/NF-κB proteins. GMc1 and DNL significantly reduced the infarct size to a similar extent ( p < 0.05) but their combined effect was greater than individual ones ( p < 0.01). Combination therapy significantly restored the left ventricular end-diastolic and developed pressures at the end of reperfusion as compared with the untreated group ( p < 0.01). Although the GMc1 and DNL reduced the levels of inflammatory cytokine TNF-α and increased the contents of antioxidant glutathione significantly, their individual effects on the reduction of protein expression of TLR4/MyD88/NF-κB pathway were not consistent. However, their combination could significantly reduce all parameters of this inflammatory pathway as compared to untreated I/R rats ( p < 0.001). Therefore, the combined treatment with GMc1 and DNL increased the potency of each intervention in protecting the aged hearts against I/R injury. Reduction in the activity of the TLR4/MyD88/NF-κB signaling pathway and subsequent modulation of the activity of inflammatory cytokines and endogenous antioxidants play an important role in this cardioprotection.

Abstract 358: Myeloid-specific Il-4 Receptor α Knockout Alters Cardiac Remodeling Post-myocardial Infarction

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jianrui Song ◽  
Thomas Vigil ◽  
Yutein Chung ◽  
Ryan Frieler ◽  
Sascha Goonewardena ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Cardiac Remodeling ◽  
Post Myocardial Infarction ◽  
Critical Determinant ◽  
Tetrazolium Chloride ◽  
Alternatively Activated Macrophages ◽  
Inflammatory Reactions ◽  
Infarct Healing ◽  
Adverse Remodeling

Introduction: Cardiac remodeling post myocardial infarction (MI) can be a critical determinant of outcome for patients with MI. Well-contained inflammation results in successful infarct healing while excessive inflammation cause adverse remodeling which leads to heart failure. Macrophages are important participants in inflammation, helping resolve pro-inflammatory reactions and performing reparative processes. Reprogramming macrophages towards a resolving and reparative phenotype is a potential therapeutic approach. We hypothesized that IL4/IL13-induced, alternatively activated macrophages (M2) have an important role in cardiac remodeling post-MI, and we tested this hypothesis in a mouse model of MI using myeloid-specific IL4 receptor α knockout mice (MyIL4RaKO). Methods: MyIL4RaKO mice were generated using IL4Ra flox/flox ;LysM-Cre. MI was induced by ligating the left anterior descending coronary artery. Hearts were cut into 1mm sections, and then stained by tetrazolium chloride for infarct size measurement. Evenly spaced radians were taken through the infarct with the center of left ventricle in 5μm heart sections, and the average infarct thickness was calculated. qPCR was used to determine gene expression. Echocardiography was performed at baseline and 3 weeks post MI. Results: Initial infarct size was not affected by IL4Ra knockout but at 1-week post MI, infarct size of MyIL4RaKO mice (16.54 ± 2.433, n=11) was shown significantly smaller than that of FC mice (24.96 ± 2.005, n=15) showing changes in remodeling (p= 0.0129). Changes in remodeling continued and at 3-week post MI, infarct thickness of MyIL4RaKO mice (0.2171 ± 0.01053, n=6) was significantly increased, compared with that of FC mice (0.3508 ± 0.03629, n=8, p= 0.0094). These changes were accompanied by MyIL4RaKO mice also showed lower level of fibrosis markers: Col1A1 and Plod2. A significantly lower ejection fraction was observed in MyIL4RaKO mice (25.46 ± 3.749, n=5) compared with FC mice (37.90 ± 2.309, n=5) at 3 weeks (p= 0.0223). Conclusions: Myeloid-specific IL4Ra knockout results in alteration of remodeling, altered fibrosis and decreased cardiac function post MI, although the cardiac hypertrophy did not show significant change.

Evaluation of the Effects of Peritoneal Lavage with Rosmarinus officinalis Extract against the Prevention of Postsurgical-Induced Peritoneal Adhesion

Planta Medica ◽  
2020 ◽  
Vol 86 (06) ◽  
pp. 405-414 ◽  
Author(s):  
Yasamin Roohbakhsh ◽  
Vafa Baradaran Rahimi ◽  
Samaneh Silakhori ◽  
Hamed Rajabi ◽  
Pouria Rahmanian-Devin ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Vehicle Group ◽  
Vascular Endothelial ◽  
Abdominal Adhesions ◽  
Peritoneal Adhesion ◽  
Tnf Α ◽  
Endothelial Growth Factor

AbstractPostoperative adhesions are regarded as the major complication following abdominal surgery. Rosmarinus officinalis has shown antioxidative and anti-inflammatory effects. Therefore, we aimed to assess the influence of 70% v/v hydro-ethanolic extract of the aerial parts of R. officinalis against postoperative abdominal adhesions in a rat model. Forty-eight male Wistar rats (190 ± 20 g) were divided into six groups of eight: group 1 = normal group, without any surgical procedures, group 2 = control group, group 3 = vehicle group, and groups 3, 4, and 5 = experimental groups receiving 2 mL of 4, 2, or 1% w/v R. officinalis treatment. Adhesion levels were macroscopically examined. Additionally, the levels of inflammatory cytokines (interleukin-6, interleukin-1β, and TNF-α), growth factors (transforming growth factor-β1, and vascular endothelial growth factor), oxidative (NO, nitric oxide and MDA, malondialdehyde), and antioxidative (GSH, glutathione) factors were evaluated. Our results revealed that the adhesion score, interleukin-6, interleukin-1β, TNF-α, transforming growth factor-β1, vascular endothelial growth factor, NO, and MDA levels were significantly increased in the vehicle group, while the GSH level was diminished. R. officinalis treatment notably ameliorated the adhesion score following postoperative abdominal adhesions compared with the vehicle group. Our results also revealed that R. officinalis markedly reduced inflammatory cytokines, oxidative factors, fibrosis, and angiogenesis biomarkers, whereas it increased the antioxidative factor. Therefore, R. officinalis may be a potential candidate for the management of postoperative peritoneal adhesion.

Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model

2004 ◽  
Vol 287 (1) ◽  
pp. G264-G273 ◽  
Author(s):  
Atul Sahai ◽  
Padmini Malladi ◽  
Hector Melin-Aldana ◽  
Richard M. Green ◽  
Peter F. Whitington
Keyword(s):  
Oxidative Stress ◽  
Mrna Expression ◽  
Nonalcoholic Steatohepatitis ◽  
Transforming Growth Factor ◽  
Control Diet ◽  
Transforming Growth Factor Β ◽  
Collagen I ◽  
Tnf Α ◽  
Th1 Cytokine

The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly defined. Feeding mice a diet deficient in methionine and choline (MCD diet) induces experimental NASH. Osteopontin (OPN) is a Th1 cytokine that plays an important role in several fibroinflammatory diseases. We examined the role of OPN in the development of experimental NASH. A/J mice were fed MCD or control diet for up to 12 wk, and serum alanine aminotransferase (ALT), liver histology, oxidative stress, and the expressions of OPN, TNF-α, and collagen I were assessed at various time points. MCD diet-fed mice developed hepatic steatosis starting after 1 wk and inflammation by 2 wk; serum ALT increased from day 3. Hepatic collagen I mRNA expression increased during 1–4 wk, and fibrosis appeared at 8 wk. OPN protein expression was markedly increased on day 1 of MCD diet and persisted up to 8 wk, whereas OPN mRNA expression was increased at week 4. TNF-α expression was increased from day 3 to 2 wk, and evidence of oxidative stress did not appear until 8 wk. Increased expression of OPN was predominantly localized in hepatocytes. Hepatocytes in culture also produced OPN, which was stimulated by transforming growth factor-β and TNF-α. Moreover, MCD diet-induced increases in serum ALT levels, hepatic inflammation, and fibrosis were markedly reduced in OPN−/− mice when compared with OPN+/+ mice. In conclusion, our results demonstrate an upregulation of OPN expression early in the development of steatohepatitis and suggest an important role for OPN in signaling the onset of liver injury and fibrosis in experimental NASH.

scholarly journals Qiliqiangxin Attenuates Cardiac Remodeling via Inhibition of TGF-β1/Smad3 and NF-κB Signaling Pathways in a Rat Model of Myocardial Infarction

2018 ◽  
Vol 45 (5) ◽  
pp. 1797-1806 ◽  
Author(s):  
Anbang Han ◽  
Yingdong Lu ◽  
Qi Zheng ◽  
Jian Zhang ◽  
YiZhou Zhao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Signaling Pathways ◽  
Rat Model ◽  
Cardiac Remodeling ◽  
Left Ventricular ◽  
Protective Effects ◽  
Tnf Α ◽  
Tgf Β1

Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has been demonstrated to be effective and safe for the treatment of chronic heart failure. Left ventricular (LV) remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after myocardial infarction (MI). Our previous studies have shown that QL exhibits cardiac protective effects against heart failure after MI. The objective of this study was to explore the effects of QL on myocardial fibrosis in rats with MI and to investigate the underlying mechanism of these effects. Methods: A rat model of acute myocardial infarction was induced by ligating the left anterior descending coronary artery. The rats were treated with QL (1.0 g/kg/day) for 4 weeks after surgery. Echocardiography and histology examination were performed to evaluate heart function and fibrosis, respectively. Protein levels of transforming growth factor-β1 (TGF-β1), phosphorylated Smad3 (p-Smad3), phosphorylated Smad7 (p-Smad7), collagen I (Col- I), alpha smooth muscle actin (a-SMA), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), nuclear factor κB (NF-κB), and phosphorylated inhibitor of kappa B alpha (p-IκBα) were measured by western blot analysis. Results: QL treatment ameliorated adverse cardiac remodeling 8 weeks after AMI, including better preservation of cardiac function, decreased inflammation, and reduced fibrosis. In addition, QL treatment reduced Col-I, a-SMA, TGF-β1, and p-Smad3 expression levels but increased p-Smad7 levels in postmyocardial infarct rat hearts. QL administration also reduced the elevated levels of cardiac inflammation mediators, such as TNF-α and IL-6, as well as NF-κB and p-IκBα expression. Conclusions: QL therapy exerted protective effects against cardiac remodeling potentially by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways, thereby preserving cardiac function, as well as reducing myocardial inflammation and fibrosis.

scholarly journals Cardioprotective Role of Colchicine Against Inflammatory Injury in a Rat Model of Acute Myocardial Infarction

2018 ◽  
Vol 23 (5) ◽  
pp. 446-455 ◽  
Author(s):  
Oussama Bakhta ◽  
Simon Blanchard ◽  
Anne-Laure Guihot ◽  
Sophie Tamareille ◽  
Delphine Mirebeau-Prunier ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Messenger Rna ◽  
Transforming Growth Factor ◽  
Ischemia Reperfusion ◽  
Interleukin 1Β ◽  
Dependent Manner ◽  
Early Reperfusion ◽  
Beneficial Effects

Background: Inflammation plays a crucial role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. A clinical trial has recently reported a smaller infarct size in a cohort of patients with ST-segment elevation myocardial infarction (MI) treated with a short colchicine course. The mechanism underlying colchicine-induced cardioprotection in the early MI phase remains unclear. We hypothesized that a short pretreatment with colchicine could induce acute beneficial effects by protecting the heart against inflammation in myocardial I/R injury. Methods and Results: Rats were subjected to 40-minute left anterior descending coronary occlusion, followed by 120-minute reperfusion. Colchicine (0.3 mg/kg) or a vehicle was administered per os 24 hours and immediately before surgery. Infarct size was significantly reduced in the colchicine group (35.6% ± 3.0% vs 46.6% ± 3.3%, P < .05). The beneficial effects of colchicine were associated with an increased systemic interleukin-10 (IL-10) level and decreased cardiac transforming growth factor-β level. Interleukin-1β was found to increase in a “time of reperfusion”-dependent manner. Colchicine inhibited messenger RNA expression of caspase-1 and pro-IL-18. Interleukin-1β injected 10 minutes prior to myocardial ischemia induced greater infarct size (58.0% ± 2.0%, P < .05) as compared to the vehicle. Colchicine combined to IL-1β injection significantly decreased infarct size (47.1% ± 2.2%, P < .05) as compared to IL-1β alone, while colchicine alone exhibited a significantly more marked cardioprotective effect than the colchicine-IL-1β association. Conclusion: The cardioprotection induced by a short colchicine pretreatment was associated with an anti-inflammatory effect in the early reperfusion phase in our rat MI model.

Abstract 3167: Serum Activin A Level Is Associated With Infarct Size In Patients With Acute Myocardial Infarction Who Undergo Successful Primary Percutaneous Coronary Intervention

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Toru Miyoshi ◽  
Satoshi Hirohata ◽  
Tadahisa Uesugi ◽  
Minoru Hirota ◽  
Hiromichi Ohnishi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Percutaneous Coronary Intervention ◽  
Infarct Size ◽  
Primary Percutaneous Coronary Intervention ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Coronary Intervention ◽  
Activin A ◽  
St Segment Elevation ◽  
Percutaneous Coronary

PURPOSE: Activin A, a member of the transforming growth factor-beta cytokine family, has been suggested to play a role in inflammation and have pleiotropic functions. We examined the alteration of serum activin A level in patients with ST-segment elevation myocardial infarction (STEMI) who received successful primary percutaneous coronary intervention (PCI) within 12 hours, and investigated whether serum activin A was associated with infarct size. METHODS: We examined 26 patients with STEMI, 20 consecutive stable angina pectoris (AP) patients and 20 normal subjects. In STEMI patients, blood samples were collected before PCI (day0) and days 1, 2, 7 and 14. Serum activin A level was measured by enzyme-linked immunoassay. Change of activin A between day 2 and day0 (delta 2d) was also examined. The serum levels of activin A were compared with infarct size, as indicated with peak CK. RESULTS: Patients with STEMI demonstrated significantly higher serum activin A level (before PCI) than control subjects and patients with AP (316±112, 369±153 and 569±272 pg/ml, p<0.001 and p=0.007, respectively). The activin A level was significantly elevated and peaked on day 0 and reduced on days 2, and then gradually increased until days 14. Log-transformed peak CK was significantly correlated with serum activin A level on day0 (r=0.55, p=0.004) and delta 2d (r=0.58, p=0.023). In stepwise analysis, serum activin A level (beta=0.37, p=0.022) as well as age, culprit lesion (LAD) and smoking was an independent predictor of peak CK. CONCLUSIONS: The findings suggest that serum activin A level was elevated in STEMI and it may be associated with infarct size in STEMI patients.

scholarly journals Transforming Growth Factor-β Blockade Down-Regulates the Renin-Angiotensin System and Modifies Cardiac Remodeling after Myocardial Infarction

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5828-5834 ◽  
Author(s):  
Leigh J. Ellmers ◽  
Nicola J. A. Scott ◽  
Satyanarayana Medicherla ◽  
Anna P. Pilbrow ◽  
Paul G. Bridgman ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Specific Inhibitor ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Type I ◽  
Angiotensin System ◽  
Renin Angiotensin

After myocardial infarction (MI), the heart may undergo progressive ventricular remodeling, resulting in a deterioration of cardiac function. TGF-β is a key cytokine that both initiates and terminates tissue repair, and its sustained production underlies the development of tissue fibrosis, particularly after MI. We investigated the effects of a novel orally active specific inhibitor of the TGF-β receptor 1 (SD-208) in an experimental model of MI. Mice underwent ligation of the left coronary artery to induce MI and were subsequently treated for 30 d after infarction with either SD-208 or a vehicle control. Blockade of TGF-β signaling reduced mean arterial pressure in all groups. SD-208 treatment after MI resulted in a trend for reduced ventricular and renal gene expression of TGF-β-activated kinase-1 (a downstream modulator of TGF-β signaling) and a significant decrease in collagen 1, in association with a marked decrease in cardiac mass. Post-MI SD-208 treatment significantly reduced circulating levels of plasma renin activity as well as down-regulating the components of the cardiac and renal renin-angiotensin system (angiotensinogen, angiotensin converting enzyme, and angiotensin II type I receptor). Our findings indicate that blockade of the TGF-β signaling pathway results in significant amelioration of deleterious cardiac remodeling after infarction.

Cardioprotective effects of nitroparacetamol and paracetamol in acute phase of myocardial infarction in experimental rats

2006 ◽  
Vol 290 (2) ◽  
pp. H517-H524 ◽  
Author(s):  
Yi Zhun Zhu ◽  
Chew Lan Chong ◽  
Shin Chet Chuah ◽  
Shan Hong Huang ◽  
Huey Shan Nai ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Neuronal Nitric Oxide Synthase ◽  
Mortality Rates ◽  
Vehicle Group ◽  
Treatment Groups ◽  
Cyclooxygenase 1 ◽  
Cardioprotective Effects ◽  
Surgery Mortality ◽  
Oxide Synthase

We aimed to determine whether nitroparacetamol (NO-paracetamol) and paracetamol exhibit cardioprotective effects. Myocardial infarction (MI) was induced in rats, and drug treatment was started 1 wk before surgery. Mortality rate and infarct size at 2 days after MI were compared. Treatment groups included vehicle (saline), paracetamol (5 mg·kg−1·day−1) and NO-paracetamol (15 mg·kg−1·day−1). Mortality rates for vehicle ( n = 80), paracetamol ( n = 79), and NO-paracetamol ( n = 76) groups were 37.5%, 21.5%, and 26.3%, respectively. Infarct size for the vehicle group was 44.8% (±6.1%) of the left ventricle (LV). For the paracetamol and NO-paracetamol groups, infarct size was 31.3% (±5.6%) and 30.7% (±8.1%) of the LV, respectively. Both paracetamol- and NO-paracetamol-treated groups showed increased activities of catalase and SOD compared with the vehicle group. They could attenuate endothelial, inducible, and neuronal nitric oxide synthase and cyclooxygenase-1 and -2 gene expression after MI. The observation indicates the potential clinical significance of the cardioprotective effects of these drugs.

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