scholarly journals VE-Cadherin Is Required for Cardiac Lymphatic Maintenance and Signaling

2021 ◽  
Author(s):  
Natalie R Harris ◽  
Natalie R Nielsen ◽  
John B Pawlak ◽  
Amir Aghajanian ◽  
Krsna Rangarajan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Signaling Pathways ◽  
Cellular Proliferation ◽  
Lymphatic Vessels ◽  
Physiological Role ◽  
Scaffolding Protein ◽  
Functional Regression ◽  
Artery Ligation ◽  
The Impact

Background: The adherens protein VE-cadherin has diverse roles in organ-specific lymphatic vessels. However, its physiological role in cardiac lymphatics and its interaction with lymphangiogenic factors, has not been fully explored. We sought to determine the spatio-temporal functions of VE-cadherin in cardiac lymphatics and mechanistically elucidate how VE-cadherin loss influences pro-lymphangiogenic signaling pathways, such as adrenomedullin (AM) and VEGF-C/VEGFR3 signaling. Methods: Cdh5 flox/flox ;Prox1CreER T2 mice were used to delete VE-cadherin in lymphatic endothelial cells (LECs) across life stages, including embryonic, postnatal and adult. Lymphatic architecture and function was characterized utilizing immunostaining and functional lymphangiography. To evaluate the impact of temporal and functional regression of cardiac lymphatics in Cdh5 flox/flox ;Prox1CreER T2 mice, left anterior descending artery ligation was performed and cardiac function and repair after myocardial infarction was evaluated by echocardiography and histology. Cellular effects of VE-cadherin deletion on lymphatic signaling pathways were assessed by knock-down of VE-cadherin in cultured LECs. Results: Embryonic deletion of VE-cadherin produced edematous embryos with dilated cardiac lymphatics with significantly altered vessel tip morphology. Postnatal deletion of VE-cadherin caused complete disassembly of cardiac lymphatics. Adult deletion caused a temporal regression of the quiescent epicardial lymphatic network which correlated with significant dermal and cardiac lymphatic dysfunction, as measured by fluorescent and quantum dot lymphangiography, respectively. Surprisingly, despite regression of cardiac lymphatics, Cdh5 flox/flox ;Prox1CreER T2 mice exhibited preserved cardiac function, both at baseline and following myocardial infarction, compared to control mice. Mechanistically, loss of VE-cadherin leads to aberrant cellular internalization of VEGFR3, precluding the ability of VEGFR3 to be either canonically activated by VEGF-C or non-canonically transactivated by AM signaling, impairing downstream processes such as cellular proliferation. Conclusions: VE-cadherin is an essential scaffolding protein to maintain pro-lymphangiogenic signaling nodes at the plasma membrane, which are required for the development and adult maintenance of cardiac lymphatics, but not for cardiac function basally or after injury.

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.

Effects of carbon nanotube-mediated Caspase3 gene silencing on cardiomyocyte apoptosis and cardiac function during early acute myocardial infarction

Nanoscale ◽  
2020 ◽  
Vol 12 (42) ◽  
pp. 21599-21604
Author(s):  
Yi Li ◽  
Hong Yu ◽  
Liang Zhao ◽  
Yuting Zhu ◽  
Rui Bai ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Gene Silencing ◽  
Ventricular Remodeling ◽  
Myocardial Cell ◽  
Coronary Artery Ligation ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Artery Ligation ◽  
Sd Rats

Caspase3 gene silencing based on the gene transfer carrier F-CNT-siCas3 had obvious protective effects on myocardial cell apoptosis, ventricular remodeling, and cardiac function in Sprague-Dawley (SD) rats after coronary artery ligation.

scholarly journals Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction

2016 ◽  
Vol 213 (7) ◽  
pp. 1353-1374 ◽  
Author(s):  
Anta Ngkelo ◽  
Adèle Richart ◽  
Jonathan A. Kirk ◽  
Philippe Bonnin ◽  
Jose Vilar ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Mast Cells ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Troponin I ◽  
Heart Function ◽  
Ischemic Disease ◽  
Cardiomyocyte Contractility ◽  
The Impact

Acute myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Inflammatory cells orchestrate postischemic cardiac remodeling after MI. Studies using mice with defective mast/stem cell growth factor receptor c-Kit have suggested key roles for mast cells (MCs) in postischemic cardiac remodeling. Because c-Kit mutations affect multiple cell types of both immune and nonimmune origin, we addressed the impact of MCs on cardiac function after MI, using the c-Kit–independent MC-deficient (Cpa3Cre/+) mice. In response to MI, MC progenitors originated primarily from white adipose tissue, infiltrated the heart, and differentiated into mature MCs. MC deficiency led to reduced postischemic cardiac function and depressed cardiomyocyte contractility caused by myofilament Ca2+ desensitization. This effect correlated with increased protein kinase A (PKA) activity and hyperphosphorylation of its targets, troponin I and myosin-binding protein C. MC-specific tryptase was identified to regulate PKA activity in cardiomyocytes via protease-activated receptor 2 proteolysis. This work reveals a novel function for cardiac MCs modulating cardiomyocyte contractility via alteration of PKA-regulated force–Ca2+ interactions in response to MI. Identification of this MC-cardiomyocyte cross-talk provides new insights on the cellular and molecular mechanisms regulating the cardiac contractile machinery and a novel platform for therapeutically addressable regulators.

Impact of Bone Marrow Mesenchymal Stem Cells That Express Vascular Endothelial Growth Factor on Cardiac Function After Myocardial Infarction

2021 ◽  
Vol 11 (1) ◽  
pp. 44-50
Author(s):  
Yongming He ◽  
Ping Li ◽  
Yunlong Chen ◽  
Youmei Li
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Cardiac Function ◽  
Troponin T ◽  
Gene Transfection ◽  
Control Group ◽  
Marrow Mesenchymal Stem Cells ◽  
The Impact

Transplanted bone marrow mesenchymal stem cells (MSCs) can differentiate into cardiomyocytes and may have the potential to replace necrotic cardiomyocytes resulting from myocardial infarction (MI). Here we established a method for transfection of MSCs with an expression vector encoding human vascular Eedothelial Ggowth Ffctor (hVEGF). We evaluated the impact of transplantation of transfected MSCs on the recovery cardiac function and angiogenesis in a rat model of MI. Rat MSCs were separated by density gradient centrifugation; their specific surface markers were examined as was their ability to differentiate. MSCs were then transfected with pcDNA 3.1-hVEGF 165 or control-containing liposomes. Rats in the experimental MI groups received transfected MSCs, MSCs alone, or gene-transfection alone; controls included a no intervention MI group and a group that was not subjected to ischemia. Among the results, MSCs were successfully isolated and cultured. Among the intervention groups, those that received transplantation of MSCs expressing hVEGF 165 included the smallest areas of infarction and demonstrated the best recovery of cardiac function overall. Moreover, capillary density detected in this group was significantly greater than in the control group and likewise greater than in rats transplanted with MSCs alone. BrdU and Troponin-T staining revealed differential increases in the number of viable cardiomyocytes within the infarction areas; some cardiomyocytes were double-positive. Likewise, evaluation using RT-PCR revealed higher expression levels of hVEGF in rats transplanted with transfected cells compared to those treated with gene transfection alone.

scholarly journals A Novel Molecular Mechanism of IKKε-Mediated Akt/mTOR Inhibition in the Cardiomyocyte Autophagy after Myocardial Infarction

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Shuai He ◽  
Jian Shen ◽  
Liangpeng Li ◽  
Yueyue Xu ◽  
Yide Cao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery Ligation ◽  
H9c2 Cells ◽  
Wild Type ◽  
Artery Ligation ◽  
Mtor Inhibition ◽  
Cardiomyocyte Autophagy ◽  
The Impact ◽  
Cardiomyocyte Survival

Autophagy of cardiomyocytes after myocardial infarction (MI) is an important factor affecting the prognosis of MI. Excessive autophagy can lead to massive death of cardiomyocytes, which will seriously affect cardiac function. IKKε plays a crucial role in the occurrence of autophagy, but the functional role in MI remains largely unknown. To evaluate the impact of IKKε on the autophagy of cardiomyocytes after MI, MI was induced by surgical left anterior descending coronary artery ligation in IKKε knockout (KO) mice and wild-type (WT) mice. Starvation of H9c2 cells with IKKε siRNA and rescued with IKKε overexpressed afterwards to test the mechanism of IKKε in autophagy in vitro. Our results demonstrated that the expression of IKKε was upregulated in mice myocardial tissues which were consistent with cardiomyocyte autophagy after MI. Significantly, the IKKε KO mice showed increased infarct size, decreased viable cardiomyocytes, and exacerbated cardiac dysfunction when compared with the wild-type mice. Western blot and electron micrography analysis also revealed that loss of IKKε induces excessive cardiomyocyte autophagy and reduced the expression of p-Akt and p-mTOR. Similar results were observed in IKKε siRNA H9c2 cells in vitro which were under starvation injury. Notably, the levels of p-Akt and p-mTOR can restore in IKKε rescued cells. In conclusion, our results indicated that IKKε protects cardiomyocyte survival by reduced autophagy following MI via regulation of the Akt/mTOR signaling pathway. Thus, our study suggests that IKKε might represent a potential therapeutic target for the treatment of MI.

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.

Enhanced constrictor responses of skeletal muscle arterioles during chronic myocardial infarction

1997 ◽  
Vol 273 (3) ◽  
pp. H1502-H1508 ◽  
Author(s):  
S. P. Didion ◽  
P. K. Carmines ◽  
H. Ikenaga ◽  
W. G. Mayhan
Keyword(s):  
Myocardial Infarction ◽  
Skeletal Muscle ◽  
Coronary Artery Ligation ◽  
Chronic Myocardial Infarction ◽  
Ang Ii ◽  
Third Order ◽  
Artery Ligation ◽  
Arteriolar Tone ◽  
The Impact

The goal of this study was to test the hypothesis that chronic myocardial infarction potentiates agonist-induced constrictor responses of rat skeletal muscle arterioles in vivo. Eight weeks after we performed coronary artery ligation or sham (control) surgery, the spinotrapezius muscle was prepared for direct visualization of the microcirculation. Diameter of third-order arterioles (40.7 +/- 0.5 microns) to topical suffusion of angiotensin II (ANG II; 0.1-10 nM), arginine vasopressin (AVP; 0.1-10 nM), endothelin-1 (ET-1; 1.0-100 pM), and the thromboxane analog U-46619 (1.0-100 nM) was measured in both groups. Myocardial-infarcted rats exhibited enhanced arteriolar constrictor responses to ANG II and AVP compared with the responses in controls. In contrast, ET-1- and U-46619-induced constrictor responses were similar in control and myocardial-infarcted rats. Additional experiments explored the impact of NG-monomethyl-L-arginine (L-NMMA; 0.1 mM) on arteriolar reactivity. In control animals, L-NMMA potentiated ANG II- and AVP-induced vasoconstriction, achieving values similar to those observed in myocardial-infarcted rats. L-NMMA did not alter vasoconstrictor responses in rats with chronic myocardial infarction. These observations suggest that enhanced agonist-induced vasoconstriction during heart failure may reflect a loss of nitric oxide-mediated modulation of arteriolar tone.

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 162: c-fos Protects the Myocardium from Ischemic Injury and Improves Cardiac Function

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Xiangru Lu ◽  
Ming Lei ◽  
Fuli Xiang ◽  
Qingping Feng
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Ischemic Injury ◽  
Coronary Artery Ligation ◽  
Area At Risk ◽  
Artery Ligation ◽  
Protein Ratio ◽  
Myocardial Apoptosis ◽  
Bax Protein

Background: c-fos is an immediate early response gene. c-Fos proteins form heterodimers with Jun family proteins, and the resulting AP-1 complexes regulate transcription by binding to the AP-1 sequence found in many cellular genes. c-fos is activated in cardiomyocytes following myocardial infarction. However, the role of c-fos in regulating cardiomyocyte survival and cardiac function post myocardial infarction (MI) is not known. In the present study, we hypothesized that c-fos protects the myocardium from ischemic injury and improves cardiac function. Methods and Results: The generation of mice with cardiomyocyte specific c-fos −/ − was achieved by crossing the floxed c-fos mice with mice over-expressing Cre recombinase under the control of α-myosin heavy chain. Wild-type (WT) littermates were used as controls. MI was induced by coronary artery ligation. Infarct size, myocardial apoptosis and cardiac function were determined at 2 days post-MI. While area at risk was similar between the 2 groups, infarct size was significantly increased in c-fos −/ − compared to WT mice (58 ± 4% vs. 44 ± 3%, P< 0.05). Myocardial caspase-3 activity and cytosolic DNA fragments in the peri-infarct region were significantly increased while Bcl-2/Bax protein ratio was significantly decreased in c-fos −/− mice ( P< 0.05). LV pressure volume relationship was assessed in vivo using a Millar pressure conductance catheter. LV end-systolic elastance ( E es ) and +d P /dt max were significantly decreased in c-fos −/− compared to WT mice (1.7 ± 0.4 vs. 5.1 ± 1.0 mmHg/μL; 4776 ± 567 vs. 7006 ± 319 mmHg/s, P< 0.01). Conclusions: Deficiency in c-fos increases infarct size and myocardial apoptosis leading to impaired cardiac function post-MI. Our results suggest that c-fos protects the myocardium from ischemic injury and improves cardiac function.

Abstract 648: Heme-oxygenase-1 Gene Expression Ameliorates Cardiac Dysfunction Following Myocardial Infarction In C57 Mice By Recruitment Of Angiogenic Factors And Angiogenesis In C57 Mice

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
David Sacerdoti ◽  
Sumit R Monu ◽  
Paola Pesce ◽  
Stephen J Peterson ◽  
Komal Sodhi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Cardiac Function ◽  
Heme Oxygenase ◽  
Angiogenic Factors ◽  
Heme Oxygenase 1 ◽  
Artery Ligation ◽  
Capillary Formation ◽  
Beneficial Effects ◽  
Angiogenic Proteins

Rational: Angiogenesis is essential in order to increase blood circulation in infarcted tissue of MI (Myocardial infarction). Increased Heme-Oxygenase (HO)-1 gene expression increases angiogenic proteins, e.g. VEGF, bFGF, EGF, angiopoietin and adiponectin. Objective: To investigate whether increased levels of HO-1, after the occurrence of a MI, improves angiogenesis and capillary formation in ischemic myocardium, thereby improving cardiac function. METHODS: Experimental MI was induced by LAD (Left anterior descending artery) ligation. C57BL6 mice were divided into 4 groups: Sham; MI; 5 days after MI treated with the HO-1 inducer, cobalt protoporphyrinIX (CoPP); and, CoPP in the presence of the HO activity inhibitor, Stannous Mesoporphyrin (SnMP). HO-1 downstream signaling proteins were determined including VEGF, CD31 and adiponectin. Echocardiography was performed weekly for 4 weeks after surgery. Results: 5 days after MI, CoPP treatment significantly increased VEGF (p<0.05 vs.MI), CD31 (p<0.05 vs.MI), and adiponectin levels (p<0.05 vs.MI). These findings were associated with a significant increase in capillary formation and blood flow in CoPP-treated animals (p<0.05 vs.MI). Echocardiography showed that left ventricle dilatation, measured as end diastolic area (EDA), was significantly reduced in CoPP- treated animals compared to MI groups (EDA: MI: 0.216±0.02cm2; MI+CoPP: 0.172±0.03 cm2; (-13%) p<0.01). This was associated with a significant decrease in apoptosis and fibrosis (P<0.05). These beneficial effects were reversed by SnMP administration. Conclusion: HO-1 improved cardiac function and enhanced angiogenesis via the recruitment of pro-angiogenic factors.

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