Date Published: June 20, 2019
Publisher: Public Library of Science
Author(s): Lina Badimon, Laura Casaní, Sandra Camino-Lopez, Oriol Juan-Babot, Maria Borrell-Pages, Masaru Katoh.
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.
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.
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.
Acute myocardial infarction leads to acute cardiac ischemic injury. Myocardial infarction usually initiates with complete coronary artery occlusion because of the rupture of an atherosclerotic plaque and the subsequent thrombotic process . The extent of the cardiac injury depends on the duration and location of the obstruction of the blood flow. Indeed, cardiomyocytes in the cardiac tissue downstream from the blocked vessels can be killed within minutes causing a massive and immediate inflammatory response that will clear the injured tissue. This response will promote the formation of a sparse cellular tissue that will be filled in by different cellular processes that include infiltration of myofibroblasts, which will deposit collagen and other extracellular matrix proteins, and activation and proliferation of endothelial cells . In an attempt to restore blood supply, new vessels will be formed in a process named angiogenesis. Approximately a week after the initial ischemic assault a scar will form in the cardiac tissue. The low regenerative capacity of the heart coupled to the extensive systemic response to preserve ventricular integrity will eventually cause a permanent loss of cardiac tissue that will lead to ventricular remodeling and heart failure. Sometimes, efficient and synchronous heart contraction is compromised by excessive scar formation that acts as a barrier to allow a correct electromechanical signaling between the healthy regions of the heart. A better understanding of the cellular and molecular mechanisms involved in cardiac repair could help design strategies to delay the onset of heart failure in infarcted patients.
We have extensively studied the role of LRP5 and the canonical Wnt pathway in Lrp5-/- mice. We have shown that LRP5 is involved in several cellular processes including inflammation, monocyte differentiation, dislypidemia and atherosclerosis progression [5, 14, 15, 38]. Activation of canonical Wnt signaling pathway by extracellular Wnt ligands or lipids is inhibited in aortas of Lrp5-/- mice but not in Wt mice . Similarly, activation of the Wnt pathway is also abolished in circulating white cells of Lrp5-/- mice . Here we show that Lrp5-/- mice have increased myocardial GSK3β transcription and protein levels opening the possibility that the previously observed inhibition of the canonical Wnt pathway in aortas and circulating white cells of Lrp5-/- mice may be due to synergic effects of the lack of LRP5 and the increased GSK3β levels. However, further work is needed to confirm this hypothesis.