scholarly journals Nobiletin Attenuates Pathological Cardiac Remodeling after Myocardial Infarction via Activating PPARγ and PGC1α

PPAR Research ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Yufei Zhou ◽  
Ting Yin ◽  
Mengsha Shi ◽  
Mengli Chen ◽  
Xiaodong Wu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Neonatal Rat ◽  
Tunel Staining ◽  
Heme Oxygenase 1 ◽  
Coronary Artery Ligation ◽  
Tetrazolium Chloride ◽  
Qrt Pcr ◽  
Downstream Effectors

Rationale. Pathological cardiac remodeling serves as a vital mechanism during the progression from myocardial infarction (MI) to chronic heart failure (CHF). Nobiletin (NOB), an active monomer extracted from the peel of citrus fruit, has been reported to have beneficial effects in cardiovascular diseases. Our study was aimed at describing the specific mechanisms through which NOB protects against pathological cardiac remodeling after MI. Materials and Methods. C57BL/6 mice were treated with coronary artery ligation to generate an MI model, followed by treatment for 3 weeks with NOB (50 mg/kg/d) or vehicle (50 mg/kg/d), with or without the peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor T0070907 (1 mg/kg/d). Cardiac function (echocardiography, survival rate, Evans blue, and triphenyl tetrazolium chloride staining), fibrosis (Masson’s trichrome staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot (WB)), hypertrophy (haematoxylin-eosin staining, wheat germ agglutinin staining, and qRT-PCR), and apoptosis (WB and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining) were evaluated. Hypoxia-induced apoptosis (TUNEL, WB) and phenylephrine- (PE-) induced pathological hypertrophy (immunofluorescence staining, qRT-PCR) models were established in primary neonatal rat ventricular myocytes (NRVMs). The effects of NOB with or without T0070907 were examined for the expression of PPARγ and PPARγ coactivator 1α (PGC1α) by WB in mice and NRVMs. The potential downstream effectors of PPARγ were further analyzed by WB in mice. Results. Following MI in mice, NOB intervention enhanced cardiac function across three predominant dimensions of pathological cardiac remodeling, which reflected in decreasing cardiac fibrosis, apoptosis, and hypertrophy decompensation. NOB intervention also alleviated apoptosis and hypertrophy in NRVMs. NOB intervention upregulated PPARγ and PGC1α in vivo and in vitro. Furthermore, the PPARγ inhibitor abolished the protective effects of NOB against pathological cardiac remodeling during the progression from MI to CHF. The potential downstream effectors of PPARγ were nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1). Conclusions. Our findings suggested that NOB alleviates pathological cardiac remodeling after MI via PPARγ and PGC1α upregulation.

scholarly journals β1-Adrenergic receptors stimulate cardiac contractility and CaMKII activation in vivo and enhance cardiac dysfunction following myocardial infarction

2009 ◽  
Vol 297 (4) ◽  
pp. H1377-H1386 ◽  
Author(s):  
ByungSu Yoo ◽  
Anthony Lemaire ◽  
Supachoke Mangmool ◽  
Matthew J. Wolf ◽  
Antonio Curcio ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Contractility ◽  
Border Zone ◽  
Tunel Staining ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cardiac Inotropy ◽  
Significant Attenuation

The β-adrenergic receptor (βAR) signaling system is one of the most powerful regulators of cardiac function and a key regulator of Ca2+ homeostasis. We investigated the role of βAR stimulation in augmenting cardiac function and its role in the activation of Ca2+/calmodulin-dependent kinase II (CaMKII) using various βAR knockouts (KO) including β1ARKO, β2ARKO, and β1/β2AR double-KO (DKO) mice. We employed a murine model of left anterior descending coronary artery ligation to examine the differential contributions of specific βAR subtypes in the activation of CaMKII in vivo in failing myocardium. Cardiac inotropy, chronotropy, and CaMKII activity following short-term isoproterenol stimulation were significantly attenuated in β1ARKO and DKO compared with either the β2ARKO or wild-type (WT) mice, indicating that β1ARs are required for catecholamine-induced increases in contractility and CaMKII activity. Eight weeks after myocardial infarction (MI), β1ARKO and DKO mice showed a significant attenuation in fractional shortening compared with either the β2ARKO or WT mice. CaMKII activity after MI was significantly increased only in the β2ARKO and WT hearts and not in the β1ARKO and DKO hearts. The border zone of the infarct in the β2ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared with the β1ARKO and DKO hearts. Taken together, these data show that cardiac function and CaMKII activity are mediated almost exclusively by the β1AR. Moreover, it appears that β1AR signaling is detrimental to cardiac function following MI, possibly through activation of CaMKII.

scholarly journals IL-33 induces type-2-cytokine phenotype but exacerbates cardiac remodeling post-myocardial infarction with eosinophil recruitment, worsened systolic dysfunction, and ventricular wall rupture

2020 ◽  
Vol 134 (11) ◽  
pp. 1191-1218 ◽  
Author(s):  
Rana Ghali ◽  
Nada J. Habeichi ◽  
Abdullah Kaplan ◽  
Cynthia Tannous ◽  
Emna Abidi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Systolic Dysfunction ◽  
Cardiac Cells ◽  
Eosinophil Infiltration ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cytokine Milieu

Abstract Myocardial infarction (MI) is the leading cause of mortality worldwide. Interleukin (IL)-33 (IL-33) is a cytokine present in most cardiac cells and is secreted on necrosis where it acts as a functional ligand for the ST2 receptor. Although IL-33/ST2 axis is protective against various forms of cardiovascular diseases, some studies suggest potential detrimental roles for IL-33 signaling. The aim of the present study was to examine the effect of IL-33 administration on cardiac function post-MI in mice. MI was induced by coronary artery ligation. Mice were treated with IL-33 (1 μg/day) or vehicle for 4 and 7 days. Functional and molecular changes of the left ventricle (LV) were assessed. Single cell suspensions were obtained from bone marrow, heart, spleen, and peripheral blood to assess the immune cells using flow cytometry at 1, 3, and 7 days post-MI in IL-33 or vehicle-treated animals. The results of the present study suggest that IL-33 is effective in activating a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. However, IL-33 administration was associated with worsened cardiac function and adverse cardiac remodeling in the MI mouse model. IL-33 administration increased infarct size, LV hypertrophy, cardiomyocyte death, and overall mortality rate due to cardiac rupture. Moreover, IL-33-treated MI mice displayed a significant myocardial eosinophil infiltration at 7 days post-MI when compared with vehicle-treated MI mice. The present study reveals that although IL-33 administration is associated with a reparative phenotype following MI, it worsens cardiac remodeling and promotes heart failure.

Abstract 213: Deletion of 12/15 Lipoxygenase and Fatty Acids Interaction Alters Leukocyte Kinetics Leading to Improved Healing Following Myocardial Infarction

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Ganesh V Halade ◽  
Vasundhara Kain ◽  
Kevin A Ingle ◽  
Janusz H Kabarowski ◽  
Stephen Barnes ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Fatty Acids ◽  
Cardiac Remodeling ◽  
Formyl Peptide Receptor ◽  
Lv Function ◽  
Heme Oxygenase 1 ◽  
Coronary Artery Ligation ◽  
Standard Diet ◽  
Resolution Of Inflammation ◽  
Infarct Area

The 12/15 lipoxygenase (LOX) enzyme catalyzes oxygenation of fatty acids to form lipid mediators leading to non-resolving inflammation. However, how 12/15LOX interacts with PUFA (polyunsaturated fatty acids) in post-myocardial infarction (MI) cardiac healing is unclear. Here we assessed the role of 12/15LOX in post-MI cardiac remodeling in a PUFA (10% w/w, 22 Kcal) enriched environment. C57BL/6J wild-type (WT) and 12/15LOX null (12/15LOX –/– ) male mice of 8-12-weeks age were fed PUFA-enriched diet for 1 month and subjected to permanent coronary artery ligation. Post-MI mice were monitored for day (d)1 or d5 along with standard diet (SD)-fed MI controls. No-MI surgery mice served as d0 controls. 12/15LOX and PUFA+12/15LOX -/- mice reduced infarcted wall thinning with decreased lung edema index at d5 post-MI (all p<0.05) despite comparable infarct area (49-52%). PUFA+WT and 12/15LOX -/- mice showed improved ejection fraction with reduced left ventricle (LV) hypertrophy index than SD+WT at d5 post-MI (p<0.05). The neutrophil density was decreased in both PUFA+WT and 12/15LOX -/- mice at d1 post-MI (P<0.05). The neutrophil clearance was rapid in 12/15LOX -/- alone and PUFA+12/15LOX -/- mice, with increases in expression of formyl peptide receptor 2 at d5 post-MI. The macrophage density was decreased in PUFA+WT and 12/15LOX -/- mice compared with their respective SD+WT control at d5 post-MI. PUFA+12/15LOX -/- mice displayed an increased expression of ccl2 (all p<0.05) in the infarct area. 12/15LOX deletion stimulated 5-LOX and heme oxygenase-1 in PUFA+12/15LOX -/- mice with increased levels of 9-and 13-hydroxyoctadecadienoic acid indicating improved resolution of inflammation at d5 post-MI. The PUFA+12/15LOX -/- mice displayed higher expression of proresolving macrophages ym-1, mrc-1 and arg-1 compared with SD+12/15LOX -/- mice at d5 post-MI (all p<0.05). Further, 12/15LOX -/- mice with or without PUFA showed reduced collagen deposition at d5 post-MI compared to SD+WT. In conclusion, deletion of 12/15LOX and short-term PUFA exposure attenuated cardiac remodeling via shortening the pro-inflammatory window, thus leading to an improved resolution of inflammation and LV function post-MI.

scholarly journals Matricellular Protein Cilp1 Promotes Myocardial Fibrosis in Response to Myocardial Infarction

2021 ◽  
Author(s):  
Qing-Jun Zhang ◽  
Yu He ◽  
Yongnan Li ◽  
Huali Shen ◽  
Ling Lin ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Heart Disease ◽  
Cardiac Function ◽  
Mechanism Of Action ◽  
Cardiac Remodeling ◽  
Cardiac Fibroblasts ◽  
Neonatal Rat ◽  
Heart Failure Patients ◽  
Mtorc1 Signaling

Rationale: Cartilage intermediate layer protein 1 (Cilp1) is a secreted extracellular matrix (ECM) protein normally associated with bone and cartilage development. Its function and mechanism of action in adult heart disease remain elusive. Objective: To establish the function and mechanism of action of Cilp1 in post-myocardial infarction (MI) cardiac remodeling. Methods and Results: We investigated the expression of Cilp1 in mouse models of pathological cardiac remodeling and human heart failure patients. Cilp1 was expressed predominantly in cardiac fibroblasts and upregulated in response to cardiac injury and in the heart and blood of heart failure patients. We generated Cilp1 knock out (KO) and transgenic (Tg) mice with N-terminal half of the protein (NCilp1) overexpressed in myofibroblasts. Cilp1 KO mice had better cardiac function, reduced number of immune cells and myofibroblasts, and enhanced microvascular survival after MI compared to wild-type (WT) littermates. Conversely, NCilp1-Tg mice had augmented loss of cardiac function, increased number of myofibroblasts and infarct size after the MI injury. RNA-seq and gene ontology analysis indicated that cell proliferation and mTORC1 signaling were downregulated in KO hearts compared to WT hearts. In vivo BrdU labeling and immunofluorescence staining showed that myofibroblast proliferation in the Cilp1 KO heart was downregulated. Biaxial mechanical testing and ECM gene expression analysis indicated that while MI caused significant stiffness in WT hearts it had little effect on KO hearts. Upregulation of collagen expression after MI injury was attenuated in KO hearts. Recombinant CILP1 protein or NCilp1-conditioned medium promoted proliferation of neonatal rat ventricular cardiac fibroblasts via the mTORC1 signaling pathway. Conclusions: Our studies established a pathological role of Cilp1 in promoting post-MI remodeling, identified a novel function of Cilp1 in promoting myofibroblast proliferation, and suggested that Cilp1 may serve as a potential biomarker for pathological cardiac remodeling and target for fibrotic heart disease.

scholarly journals Voluntary exercise and cardiac remodeling in a myocardial infarction model

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 545-555
Author(s):  
Hamad Al Shahi ◽  
Tomoyasu Kadoguchi ◽  
Kazunori Shimada ◽  
Kosuke Fukao ◽  
Satoshi Matsushita ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Skeletal Muscles ◽  
Wheel Running ◽  
Voluntary Exercise ◽  
Fibroblast Growth Factor 21 ◽  
Expression Levels ◽  
Factor Α ◽  
Necrosis Factor

AbstractWe investigated the effects of voluntary exercise after myocardial infarction (MI) on cardiac function, remodeling, and inflammation. Male C57BL/6J mice were divided into the following four groups: sedentary + sham (Sed-Sh), sedentary + MI (Sed-MI), exercise + sham (Ex-Sh), and exercise + MI (Ex-MI). MI induction was performed by ligation of the left coronary artery. Exercise consisting of voluntary wheel running started after the operation and continued for 4 weeks. The Ex-MI mice had significantly increased cardiac function compared with the Sed-MI mice. The Ex-MI mice showed significantly reduced expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 in the infarcted area of the left ventricle compared with the Sed-MI mice. In the Ex-MI mice, the expression levels of fibrosis-related genes including collagen I and III were decreased compared to the Sed-MI mice, and the expression levels of IL-1β, IL-6, follistatin-like 1, fibroblast growth factor 21, and mitochondrial function-related genes were significantly elevated in skeletal muscle compared with the Sed mice. The plasma levels of IL-6 were also significantly elevated in the Ex-MI group compared with the Sed-MI groups. These findings suggest that voluntary exercise after MI may improve in cardiac remodeling associated with anti-inflammatory effects in the myocardium and myokine production in the skeletal muscles.

scholarly journals Endothelial β1 Integrin-Mediated Adaptation to Myocardial Ischemia

2021 ◽  
Author(s):  
Carina Henning ◽  
Anna Branopolski ◽  
Paula Follert ◽  
Oksana Lewandowska ◽  
Aysel Ayhan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Myocardial Ischemia ◽  
Cardiac Function ◽  
Integrin Subunit ◽  
Β1 Integrin ◽  
Human Coronary Artery ◽  
Tetrazolium Chloride ◽  
Magnetic Resonance Imaging Mri ◽  
Interfering Rna

Abstract Background Short episodes of myocardial ischemia can protect from myocardial infarction. However, the role of endothelial β1 integrin in these cardioprotective ischemic events is largely unknown. Objective In this study we investigated whether endothelial β1 integrin is required for cardiac adaptation to ischemia and protection from myocardial infarction. Methods Here we introduced transient and permanent left anterior descending artery (LAD) occlusions in mice. We inhibited β1 integrin by intravenous injection of function-blocking antibodies and tamoxifen-induced endothelial cell (EC)-specific deletion of Itgb1. Furthermore, human ITGB1 was silenced in primary human coronary artery ECs using small interfering RNA. We analyzed the numbers of proliferating ECs and arterioles by immunohistochemistry, determined infarct size by magnetic resonance imaging (MRI) and triphenyl tetrazolium chloride staining, and analyzed cardiac function by MRI and echocardiography. Results Transient LAD occlusions were found to increase EC proliferation and arteriole formation in the entire myocardium. These effects required β1 integrin on ECs, except for arteriole formation in the ischemic part of the myocardium. Furthermore, this integrin subunit was also relevant for basal and mechanically induced proliferation of human coronary artery ECs. Notably, β1 integrin was needed for cardioprotection induced by transient LAD occlusions, and the absence of endothelial β1 integrin resulted in impaired growth of blood vessels into the infarcted myocardium and reduced cardiac function after permanent LAD occlusion. Conclusion We showed that endothelial β1 integrin is required for adaptation of the heart to cardiac ischemia and protection from myocardial infarction.

scholarly journals PO-173 The Effects of Interval Exercise on oxidative stress and Smyd1-related myocardial hypertrophy in Rats with Myocardial Infarction

2018 ◽  
Vol 1 (4) ◽  
Author(s):  
Qiaoqin Liang ◽  
Mengxin Cai ◽  
Jiaqi Zhang ◽  
Zhenjun Tian
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Cardiac Function ◽  
Stress Level ◽  
Exercise Group ◽  
Control Group ◽  
Coronary Artery Ligation ◽  
Interval Exercise ◽  
Oxidative Stress Level ◽  
Sarcomere Assembly

Objective This study was carried out to investigate interval exercise on Smyd1 expression and F-actin sarcomere assembly in non-infarcted myocardium of normal and myocardial infarction(MI) rats and its possible mechanism. Methods Male SD rats were randomly divided into normal control group (C), normal interval exercise group (CE), sham-operated group (S), MI group (MI), MI with interval exercise group (ME) and MI with ROS Tempol group (MT), n=10. MI model was established by left anterior descending coronary artery ligation. Interval exercise was carried out on a small animal treadmill. MT group was given an oral solution of Tempol (2mmol/L). Hemodynamics was performed to evaluate cardiac function. HE and Masson staining were used to analyze the cross-sectional area (CSA) of cardiomyocytes and collagen volume fraction, respectively. T-SOD and MDA kits were used to detect oxidative stress. H9C2 cells were treated with H2O2. Immunofluorescence staining was used to determine Smyd1 expression and F-actin sarcomere assembly. RT-qPCR and Western blotting were used to detect the gene or protein expression of Smyd1, Trx1, Hsp90, MuRF1, cTnI, α-actinin and BNP. Results Smyd1, Trx1, Hsp90, MuRF1 and BNP expression in the peri-infarcted area were up-regulated, but cTnI and α-actinin expression and F-actin assembly were decreased. The cardiac function was reduced. Both interval exercise and Tempol intervention significantly increase the CSA and expression of Smyd1, Trx1, cTnI and α-actinin, improve the antioxidation capacity and F-actin sarcomere assembly and cardiac function, reduce the expression of Hsp90, MuRF1, BNP and ROS level, and inhibit the fibrosis of myocardium. The oxidative stress level was closely related to the Smyd1 expression. Improvement of cardiac function were correlated with Smyd1 expression. H2O2 can induce oxidative stress injuries of H9C2, and its closely related to cardiomyocytes oxidative stress level and Smyd1 expression. Conclusions Interval exercise could promote antioxidant capability and physiological cardiomyocyte hypertrophy, regulate the expression of Smyd1, Hsp90 and MuRF1 in infarcted heart; so as to improve the cardiac function. Smyd1 may participate in pathologic hypertrophy of cardiomyocytes caused by oxidative stress.

Abstract 855: Circulating Mesoangioblasts Differentiate Into Cardiac Myocytes And Improve Function After Acute Myocardial Infarction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Masayoshi Iwasaki ◽  
Masamichi Koyanagi ◽  
Stefan Rapp ◽  
Corina Schuetz ◽  
Philipp Bushoven ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Troponin T ◽  
Marker Gene ◽  
Left Ventricular ◽  
Cardiac Differentiation ◽  
Neonatal Rat ◽  
Stem Cell Markers ◽  
Rt Pcr ◽  
Rat Cardiomyocytes

Mesoangioblasts (MAB) are vessel-associated cells identified during embryonic development. In contrast to hemangioblasts, MAB express mesenchymal (CD73) and endothelial marker, but lack the hematopoietic marker CD45. We recently identified circulating MAB in children. Children-derived MAB showed vigorous proliferation capacity and high telomerase activity. However, the potential of cardiac differentiation in these cells was not elucidated. Therefore, we tested the capacity of children-derived MAB to aquire a cardiomyogenic phenotype. MAB expressed several cardiac transcription factors such as Nkx2.5, GATA4 and MEF2C and the stem cell markers c-kit and islet-1. In order to assess cardiac differentiation capacity, we performed co-culture assays with neonatal rat cardiomyocytes (CM). Immunochemical analysis revealed that MAB expressed cardiac α-sarcomeric actinin 6 days after co-culture. Moreover, human troponin T (TnT) was expressed as demonstrated by human specific RT-PCR. To confirm these data, we examined TnT expression in MAB isolated of a 2 years old patient with a known mutation of TnT. Sequences of the cloned RT-PCR products were identical to human TnT except for the known mutation providing genetic proof of concept for cardiac differentiation. In order to exclude fusion between MAB and CM as a mechanism, we used paraformaldehyde-fixed CM as scaffold. In this assay, human TnT also was detected, indicating that differentiation is sufficient to induce cardiac marker gene expression. Next, we tested the effect of MAB to improve cardiac function. MAB were injected intramuscularly in nude mice after myocardial infarction. Functional analysis using Millar catheter 2 weeks after infarction demonstrated that cell therapy lowered filling pressure and preserved diastolic function when compared to the PBS injected group (LVEDP: −20.3%, tau: −20.6%, vs PBS injected heart). Furthermore, left ventricular volume was also decreased (LVEDV/weight −27.3%). In summary, children-derived MAB express cardiac-specific genes after co-culture with CM and improved cardiac function in vivo. Given that MAB can be easily isolated and expanded from peripheral blood, these cells might be suitable to augment cardiac repair in children with heart failure.

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