Deletion of Extra Domain A of Fibronectin Reduces Acute Myocardial Ischaemia/Reperfusion Injury in Hyperlipidaemic Mice by Limiting Thrombo-Inflammation

Chorawala, Mehul R.; Prakash, Prem; Doddapattar, Prakash; Jain, Manish; Dhanesha, Nirav; Chauhan, Anil K.

doi:10.1055/s-0038-1661353

Cited by 22 publications

(27 citation statements)

References 39 publications

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“…Deletion of fibronectin-EDA is associated with less adverse remodeling and heart failure in a MI mouse model of permanent coronary ligation ( 35 ). Fibronectin-EDA also showed to contribute to myocardial IRI via TLR4-mediated signaling in hyperlipidemic mice ( 36 ) and administration of an anti-fibronectin antibody, 15 min post-reperfusion, reduced IS following ischemia/reperfusion in the same mouse model as well ( 36 ). In HTx, rodent studies revealed involvement in chronic cardiac allograft rejection ( 37 , 38 ).…”

Section: Damage-associated Molecular Patterns Related To Myocardial Imentioning

confidence: 99%

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

et al. 2020

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In the setting of myocardial infarction (MI), ischemia reperfusion injury (IRI) occurs due to occlusion (ischemia) and subsequent re-establishment of blood flow (reperfusion) of a coronary artery. A similar phenomenon is observed in heart transplantation (HTx) when, after cold storage, the donor heart is connected to the recipient’s circulation. Although reperfusion is essential for the survival of cardiomyocytes, it paradoxically leads to additional myocardial damage in experimental MI and HTx models. Damage (or danger)-associated molecular patterns (DAMPs) are endogenous molecules released after cellular damage or stress such as myocardial IRI. DAMPs activate pattern recognition receptors (PRRs), and set in motion a complex signaling cascade resulting in the release of cytokines and a profound inflammatory reaction. This inflammatory response is thought to function as a double-edged sword. Although it enables removal of cell debris and promotes wound healing, DAMP mediated signalling can also exacerbate the inflammatory state in a disproportional matter, thereby leading to additional tissue damage. Upon MI, this leads to expansion of the infarcted area and deterioration of cardiac function in preclinical models. Eventually this culminates in adverse myocardial remodeling; a process that leads to increased myocardial fibrosis, gradual further loss of cardiomyocytes, left ventricular dilation and heart failure. Upon HTx, DAMPs aggravate ischemic damage, which results in more pronounced reperfusion injury that impacts cardiac function and increases the occurrence of primary graft dysfunction and graft rejection via cytokine release, cardiac edema, enhanced myocardial/endothelial damage and allograft fibrosis. Therapies targeting DAMPs or PRRs have predominantly been investigated in experimental models and are potentially cardioprotective. To date, however, none of these interventions have reached the clinical arena. In this review we summarize the current evidence of involvement of DAMPs and PRRs in the inflammatory response after MI and HTx. Furthermore, we will discuss various current therapeutic approaches targeting this complex interplay and provide possible reasons why clinical translation still fails.

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Section: Damage-associated Molecular Patterns Related To Myocardial Imentioning

confidence: 99%

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

et al. 2020

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“…Fn-EDA is an endogenous ligand for TLR4 32 and known to promote inflammation via TLR4 expressed on hematopoietic cells in experimental models. 5,6 Together our data suggests that Fn-EDA in the plasma exacerbates stroke outcome by promoting post-ischemic thrombosis and vascular inflammation.…”

Section: Discussionmentioning

confidence: 61%

“…The extracellular matrix protein fibronectin (Fn) is known to contribute to inflammation and thrombosis. [4][5][6] Fn exists in multiple isoforms that are generated by alternative processing of a single primary transcript at three sites: Extra Domain A (EDA), Extra Domain B (EDB), and the Type III Homologies Connecting Segment (IIICS). Two primary forms of FN isoforms exist in human and mice: 1) plasma Fn, which does not contain EDA and EDB.…”

Section: Introductionmentioning

confidence: 99%

Fn-EDA (Fibronectin Containing Extra Domain A) in the Plasma, but Not Endothelial Cells, Exacerbates Stroke Outcome by Promoting Thrombo-Inflammation

Dhanesha

Chorawala

Jain

et al. 2019

Stroke

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Background and Purpose-Cellular fibronectin containing extra domain A (Fn-EDA) is expressed in activated endothelial cells and elevated in circulation in patients with cardiovascular diseases. While global deficiency of Fn-EDA in mice improves stroke outcome, the specific contribution of plasma versus endothelium Fn-EDA in stroke outcome is currently unknown. We investigated the role of plasma versus endothelial Fn-EDA in stroke exacerbation in the comorbid condition of hyperlipidemia. Methods-We generated novel plasma Fn-EDA −/− (Fn-EDA fl/fl Alb Cre) and endothelial Fn-EDA −/− (Fn-EDA fl/fl Tie2 Cre) strains on hyperlipidemic apolipoprotein E-deficient (Apoe −/−) background. By following the STAIR guidelines, we evaluated stroke outcome in male and female mice. Susceptibility to ischemia/reperfusion injury was evaluated in two different models of stroke: intraluminal monofilament and embolic model, on day 1, 3 and 7. Quantitative assessment of stroke outcome was evaluated by measuring infarct volume (by MRI), cerebral blood flow (CBF, by laser speckle imaging), neurological and sensory-motor outcome, and post-ischemic thrombo-inflammation (platelet thrombi, fibrin, neutrophil, phospho-NFκB, TNFα, and IL-1β). Results-Stroke outcome was comparable in Apoe −/− Fn-EDA fl/fl Tie2 Cre and control Apoe −/− Fn-EDA fl/fl mice suggesting endothelial Fn-EDA does not contribute to stroke. Apoe −/− Fn-EDA fl/fl Alb Cre mice exhibited significantly smaller infarcts and improved neurological and sensory-motor outcome at days 1, 3 and 7 in monofilament and embolic models of stroke. Improved stroke outcome was concomitant with enhanced survival, and decreased post-ischemic thrombo-inflammatory response (P<0.05 versus Apoe −/− Fn-EDA fl/fl). No sex-based differences were observed. Laser speckle imaging revealed significantly improved regional CBF at 1 hour in Apoe −/− Fn-EDA fl/fl Alb Cre mice suggesting plasma Fn-EDA promotes post-ischemic secondary thrombosis. Co-infusion of anti-Fn-EDA antibody with recombinant tissue plasminogen activator (rtPA) in Apoe −/− mice, 1 hour after embolization, improved stroke outcome with enhanced survival and improved neurological outcome (P<0.05 versus rtPA).

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“…MIRI is an important cause of myocardial damage and it is an unsolved problem in clinical practice (24). Inflammation has been identified to serve a crucial role in MIRI and a persistent proinflammatory reaction promotes a series of complications following reperfusion therapy (25,26). Therefore, effectively decreasing inflammation may be an important therapeutic target to improve the outcomes for MIRI.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of DEC1 by RNA interference attenuates ischemia/reperfusion‑induced myocardial inflammation by inhibiting the TLR4/NF‑κB signaling pathway

Wang

Zhang

et al. 2020

Exp Ther Med

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Inflammation has been implicated in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury (MIRI). Previous studies have confirmed that deleted in esophageal cancer 1 (DEC1) is an important transcription factor in inflammation. However, the role of DEC1 in MIRI remains unclear. The present study aimed to determine whether the downregulation of DEC1 by RNA interference alleviated inflammation to protect against MIRI. Adult Sprague-Dawley rats (n=48) were randomly divided into four groups: Sham; I/R; adenovirus expressing green fluorescent protein control (Ad-G-Control); and DEC1-targeting RNA interference (Ad-G-DEC1) groups. Following gene delivery 4 days later, the rat myocardial I/R model was established and myocardial enzymes [creatine kinase (CK) and lactate dehydrogenase (LDH)] were detected. Hematoxylin and eosin (H&E) staining was performed to evaluate the myocardial damage and the infarct area was assessed using Evans Blue/triphenyltetrazolium chloride staining. The inflammatory mediators interleukin (IL)-β and tumor necrosis factor (TNF)-α were also detected using ELISA kits to assess the inflammatory response. Finally, western blotting and reverse transcription-quantitative PCR were used to analyze the expression levels of associated proteins and mRNAs. Ad-G-DEC1 RNA interference markedly decreased DEC1 expression levels. In addition, following the downregulation of DEC1 expression, the infarct size, CK, LDH, Toll-like receptor (TLR)4, NF-κB, IL-β and TNF-α levels were all significantly decreased. In conclusion, the results of the present study suggested that the downregulation of DEC1 may decrease the inflammation by suppressing the TLR4/NF-κB signaling pathway, which may represent a therapeutic target for MIRI.

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Deletion of Extra Domain A of Fibronectin Reduces Acute Myocardial Ischaemia/Reperfusion Injury in Hyperlipidaemic Mice by Limiting Thrombo-Inflammation

Abstract: Fn-EDA exacerbates TLR4-dependent myocardial I/R injury by promoting post-ischaemic thrombo-inflammatory response. Targeting Fn-EDA may reduce cardiac damage following coronary artery re-canalization after acute MI.

Cited by 22 publications

References 39 publications

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

Fn-EDA (Fibronectin Containing Extra Domain A) in the Plasma, but Not Endothelial Cells, Exacerbates Stroke Outcome by Promoting Thrombo-Inflammation

Downregulation of DEC1 by RNA interference attenuates ischemia/reperfusion‑induced myocardial inflammation by inhibiting the TLR4/NF‑κB signaling pathway

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