LRP5/canonical Wnt signalling and healing of ischemic myocardium

Borrell-Pagès, María; Vilahur, Gemma; Romero, July Carolina; Béjar, Maria Teresa; Badimon, Lina

doi:10.1007/s00395-016-0585-y

Cited by 30 publications

(25 citation statements)

References 51 publications

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“…Myocardial damage, measured blindly as previously done in [16], was significantly larger in Lrp5 -/- mice than in Wt mice. However myocardial damage assessment was independent of CHIR99021 treatments and GSK3β levels.…”

Section: Resultsmentioning

confidence: 89%

“…We have recently described the prosurvival function of the canonical Wnt pathway in vascular cells of atherosclerotic lesions [5, 13–15] and in myocardial injury (MI) [16]. Expression of several Wnt pathway proteins such as β-catenin and Dvl are increased in the damaged tissue after experimental myocardial infarction-induction [17–20].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the transfer of β-catenin (with a constitutively active adenovirus) in a rat myocardial infarction model induced a reduction in infarct size [23]. We have previously evidenced that mice lacking Lrp5 ( Lrp5 -/- mice) show more myocardial damage than Wt mice [16] suggesting that canonical Wnt signaling activation is cardioprotective. A possible explanation for these apparent contradictory results is that experiments were performed in different animal models with different myocardial injury-induction times and used different parameters to analyze Wnt pathway modulation.…”

Section: Introductionmentioning

confidence: 99%

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GSK3β inhibition and canonical Wnt signaling in mice hearts after myocardial ischemic damage

et al. 2019

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Aims Myocardial infarction induces myocardial injury and tissue damage. During myocardial infarction strong cellular response is initiated to salvage the damaged tissues. This response is associated with the induction of different signaling pathways. Of these, the canonical Wnt signaling is increasingly important for its prosurvival cellular role, making it a good candidate for the search of new molecular targets to develop therapies to prevent heart failure in infarcted patients. Methods Herein we report that GSK3β regulates the canonical Wnt signaling in C57Bl6 mice hearts. GSK3β is a canonical Wnt pathway inhibitor. Using GSK3β inhibitors and inducing myocardial injury (MI) in Lrp5 -/- mice model we show that GSK3β phosphorylation levels regulate downstream canonical Wnt pathway genes in the ischemic heart. In the setting of MI, myocardial damage assessment usually correlates with functional and clinical outcomes. Therefore, we measured myocardial injury size in Wt and Lrp5 -/- mice in the presence and absence of two different GSK3 inhibitors prior to MI. Myocardial injury was independent of GSK3 inhibitor treatments and GSK3β expression levels. Results These studies support a central role for GSK3β in the activation of the canonical Wnt pathway in the Wt heart. Although LRP5 is protective against myocardial injury, GSK3β expression levels do not regulate heart damage.

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Section: Resultsmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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GSK3β inhibition and canonical Wnt signaling in mice hearts after myocardial ischemic damage

et al. 2019

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“…In the same study, deletion of LRP5 was found to have a deleterious effect on infarct healing in mice. Moreover, human hearts explanted due to ischemic cardiomyopathy expressed higher levels of LRP5 and β -catenin compared with dilated cardiomyopathy ( Borrell-Pages et al, 2016b ). These results could be confirmed using mice carrying a cardiomyocyte-specific deletion of LRP5 and 6 ( Wo et al, 2016 ).…”

Section: Wnt Signaling In Cardiac Diseasementioning

confidence: 99%

WNT Signaling in Cardiac and Vascular Disease

et al. 2017

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WNT signaling is an elaborate and complex collection of signal transduction pathways mediated by multiple signaling molecules. WNT signaling is critically important for developmental processes, including cell proliferation, differentiation and tissue patterning. Little WNT signaling activity is present in the cardiovascular system of healthy adults, but reactivation of the pathway is observed in many pathologies of heart and blood vessels. The high prevalence of these pathologies and their significant contribution to human disease burden has raised interest in WNT signaling as a potential target for therapeutic intervention. In this review, we first will focus on the constituents of the pathway and their regulation and the different signaling routes. Subsequently, the role of WNT signaling in cardiovascular development is addressed, followed by a detailed discussion of its involvement in vascular and cardiac disease. After highlighting the crosstalk between WNT, transforming growth factor-β and angiotensin II signaling, and the emerging role of WNT signaling in the regulation of stem cells, we provide an overview of drugs targeting the pathway at different levels. From the combined studies we conclude that, despite the sometimes conflicting experimental data, a general picture is emerging that excessive stimulation of WNT signaling adversely affects cardiovascular pathology. The rapidly increasing collection of drugs interfering at different levels of WNT signaling will allow the evaluation of therapeutic interventions in the pathway in relevant animal models of cardiovascular diseases and eventually in patients in the near future, translating the outcomes of the many preclinical studies into a clinically relevant context.

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“…Subsequent activation of the canonical Wnt-signaling pathway may protect against postischemic damage, because LRP-5 knockout mice had larger infarcts compared to wild-type mice [19]. Whether PCSK9 is involved in the myocardial effects of LRP-5 remains to be established.…”

Section: Pcsk9 Effects Distinct From Hepatic Ldlr Regulationmentioning

confidence: 99%

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

et al. 2017

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Ischemic heart disease is the main cause of death worldwide and is accelerated by increased levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL-C through its ability to induce degradation of the LDL receptor (LDLR) in the lysosome of hepatocytes. Only in the last few years, a number of breakthroughs in the understanding of PCSK9 biology have been reported illustrating how PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Two humanized antibodies directed against the LDLR-binding site in PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics are climbing up the phases of clinical trials. The first outcome data of the PCSK9 inhibitor evolocumab reported a significant reduction in the composite endpoint (cardiovascular death, myocardial infarction, or stroke) and further outcome data are awaited. Meanwhile, it became evident that PCSK9 has (patho)physiological roles in several cardiovascular cells. In this review, we summarize and discuss the recent biological and clinical data on PCSK9, the regulation of PCSK9, its extra-hepatic activities focusing on cardiovascular cells, molecular concepts to target PCSK9, and finally briefly summarize the data of recent clinical studies.

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LRP5/canonical Wnt signalling and healing of ischemic myocardium

Cited by 30 publications

References 51 publications

GSK3β inhibition and canonical Wnt signaling in mice hearts after myocardial ischemic damage

GSK3β inhibition and canonical Wnt signaling in mice hearts after myocardial ischemic damage

WNT Signaling in Cardiac and Vascular Disease

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

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