Runx1 Deficiency Protects Against Adverse Cardiac Remodeling After Myocardial Infarction

McCarroll, Charlotte S.; He, Weidong; Foote, Kirsty; Bradley, Ashley; McGlynn, Karen; Vidler, Francesca; Nixon, Colin; Nather, Katrin; Fattah, Caroline; Riddell, Alexandra; Bowman, Peter R. T.; Elliott, Elspeth B.; Bell, Margaret; Hawksby, C.; MacKenzie, Scott; Morrison, Liam J.; Terry, Anne; Blyth, Karen; Smith, Godfrey L.; McBride, Martin W.; Kubin, Thomas; Braun, Thomas; Nicklin, Stuart A.; Cameron, Ewan R.; Loughrey, Christopher M.

doi:10.1161/circulationaha.117.028911

Cited by 75 publications

(114 citation statements)

References 20 publications

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“…In a previous study, cardiomyocyte specific knock-out of Runx1 in the mouse showed increased sarcoplasmic reticulum calcium content and sarcoplasmic reticulum-mediated calcium release in the myocardium after injury (29). Correspondingly, we found increased expression of calciumresponsive genes in the citrine-positive myocardium of our zebrafish runx1 mutant after injury; including Calmodulins calm1b, calm2b and calm3a (Fig.…”

Section: Upregulation Of Plasminogen Receptor Annexin A2 In the Runx1supporting

confidence: 76%

“…These data are supported by the results from myocardial specific Runx1 knock-out mice, which were found to exhibit improved calcium handling in cardiomyocytes, with increased sarcoplasmic reticulum calcium content and sarcoplasmic reticulum-mediated calcium release. The elevated calcium levels protected the cardiomyocytes against adverse remodelling after MI, preserving cardiomyocyte contraction (29). The cardioprotective effect of increased calcium levels can explain the ability of runx1 mutant cardiomyocytes to survive cryoinjury.…”

Section: Discussionmentioning

confidence: 97%

“…In contrast, our findings demonstrate the opposite in that loss of runx1 results in enhanced heart regeneration, by increasing myocardial proliferation, increasing myocardial survival, and by altering scar composition as discussed above. This poses the question as to why Runx1 is specifically upregulated during both zebrafish heart regeneration and mammalian heart repair (24,25,29,44) when it seems to function to inhibit key regenerative processes. The answer might lie in the fact that absence of runx1 causes increased proliferation and upregulation of the Annexin 2a receptor, which is strongly linked to proliferation in cancer (43).…”

Section: Discussionmentioning

confidence: 99%

“…In the heart, Runx1 is expressed in neonatal mouse cardiomyocytes and is upregulated in zebrafish, adult mouse, rat and human cardiomyocytes after injury (24)(25)(26)(27)(28). Conditional Runx1 deficiency in mouse cardiomyocytes has been demonstrated to protect the mouse against the negative consequences of cardiac remodelling after myocardial infarction (29). Although no changes in injury size were found between myocardial conditional Runx1 knock-out and control mice, the remaining cardiomyocytes displayed improved calcium handling, accompanied by improved wall thickness and contractile function compared to wild-type (29).…”

Section: Introductionmentioning

confidence: 99%

“…Conditional Runx1 deficiency in mouse cardiomyocytes has been demonstrated to protect the mouse against the negative consequences of cardiac remodelling after myocardial infarction (29). Although no changes in injury size were found between myocardial conditional Runx1 knock-out and control mice, the remaining cardiomyocytes displayed improved calcium handling, accompanied by improved wall thickness and contractile function compared to wild-type (29). However, as the knockout was cardiomyocyte specific, the involvement of other cardiac cell-types was not investigated.…”

Section: Introductionmentioning

confidence: 99%

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Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

Koth

Wang

Killen

et al. 2019

Preprint

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Runx1 is a transcription factor that plays a key role in determining the proliferative and differential state of multiple cell-types, during both development and adulthood. Here, we report how runx1 is specifically upregulated at the injury site during zebrafish heart regeneration, but unexpectedly, absence of runx1 results in enhanced regeneration. Using single cell sequencing, we found that the wild-type injury site consists of Runx1-positive endocardial cells and thrombocytes that induce expression of smooth muscle and collagen genes without differentiating into myofibroblasts. Both these populations are absent in runx1 mutants, resulting in a less collagenous and fibrinous scar. The reduction in fibrin in the mutant is further explained by reduced myofibroblast formation and by upregulation of components of the fibrin degradation pathway, including plasminogen receptor Annexin 2A as well as downregulation of plasminogen activator inhibitor serpine1 in myocardium and endocardium, resulting in increased levels of Plasminogen. In addition, we find enhanced myocardial proliferation as well as increased myocardial survival in the mutant. Our findings suggest that Runx1 controls the regenerative response of multiple cardiac cell-types and that targeting Runx1 is a novel therapeutic strategy to induce endogenous heart repair.

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Section: Upregulation Of Plasminogen Receptor Annexin A2 In the Runx1supporting

confidence: 76%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

Koth

Wang

Killen

et al. 2019

Preprint

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Activation of Toll‐like receptor 7 provides cardioprotection in septic cardiomyopathy‐induced systolic dysfunction

Xie

et al. 2021

Clinical & Translational Med

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Inhibition of RUNX1 blocks the differentiation of lung fibroblasts to myofibroblasts

Dubey

Umeshappa

et al. 2022

Journal Cellular Physiology

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Pathological fibrosis contributes to progression of various diseases, for which the therapeutic options are limited. Idiopathic pulmonary fibrosis (IPF) is one such progressive and fatal interstitial fibrotic disease that is often characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to stiff lung tissue and impaired gas exchange. However, the molecular mechanisms underlying IPF progression remain largely unknown. In this study, we determined the role of Runt‐related transcription factor 1 (RUNX1), an evolutionarily conserved transcription factor, in the differentiation of human lung fibroblasts (HLFs) in vitro and in an animal model of bleomycin (BLM)‐induced lung fibrosis. We observed that the expression of RUNX1 was significantly increased in the lungs of BLM‐injected mice as compared to saline‐treated mice. Furthermore, HLFs stimulated with transforming growth factor β (TGF‐β) showed significantly higher RUNX1 expression at both mRNA and protein levels, and compartmentalization in the nucleus. Inhibition of RUNX1 in HLFs (using siRNA) showed a significant reduction in the differentiation of fibroblasts into myofibroblasts as evidenced by reduced expression of alpha‐smooth muscle actin (α‐SMA), TGF‐β and ECM proteins such as fibronectin 1 (FN1), and collagen 1A1 (COL1A1). Mechanistic studies revealed that the increased expression of RUNX1 in TGF‐β‐stimulated lung fibroblasts is due to enhanced mRNA stability of RUNX1 through selective interaction with the RNA‐binding profibrotic protein, human antigen R (HuR). Collectively, our data demonstrate that increased expression of RUNX1 augments processes involved in lung fibrosis including the differentiation of fibroblasts into collagen‐synthesizing myofibroblasts. Our study suggests that targeting RUNX1 could limit the progression of organ fibrosis in diseases characterized by abnormal collagen deposition.

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Runx1 Deficiency Protects Against Adverse Cardiac Remodeling After Myocardial Infarction

Abstract: Supplemental Digital Content is available in the text.

Cited by 75 publications

References 20 publications

Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration

Activation of Toll‐like receptor 7 provides cardioprotection in septic cardiomyopathy‐induced systolic dysfunction

Inhibition of RUNX1 blocks the differentiation of lung fibroblasts to myofibroblasts

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