Key result
Endothelial FLNA deletion in mice worsens post-MI LV dysfunction driven by increased scar formation.
Why the study?
Does endothelial deletion of FLNA impair left ventricular remodelling and cardiac function after myocardial infarction in mice?
Does endothelial deletion of FLNA impair left ventricular remodelling and cardiac function after myocardial infarction in mice?
Endothelial filamin A plays a crucial role in post-MI left ventricular remodeling, and its deficiency aggravates cardiac dysfunction and heart failure.
Endothelial FLNA loss worsens post-MI remodeling in mice; hypothesis-generating for therapeutic targeting, no clinical implications yet.
AIMS: Actin-binding protein filamin A (FLNA) regulates signal transduction important for cell locomotion, but the role of FLNA after myocardial infarction (MI) has not been explored. The main purpose of this study was to determine the impact of endothelial deletion of FLNA on post-MI remodelling of the left ventricle (LV). METHODS AND RESULTS: We found that FLNA is expressed in human and mouse endothelial cells (ECs) during MI. To determine the biological significance of endothelial expression of FLNA, we used mice that are deficient for endothelial FLNA by cross-breeding adult mice expressing floxed Flna (Flna(o/fl)) with mice expressing Cre under the vascular endothelial-specific cadherin promoter (VECadCre+). Male Flna(o/fl) and Flna(o/fl)/VECadCre+ mice were subjected to permanent coronary artery ligation to induce MI. Flna(o/fl)/VECadCre+ mice that were deficient for endothelial FLNA exhibited larger and thinner LV with impaired cardiac function as well as elevated plasma levels of NT-proBNP and decreased secretion of VEGF-A. The number of capillary structures within the infarcted areas was reduced in Flna(o/fl)/VECadCre+ hearts. ECs silenced for Flna mRNA expression exhibited impaired tubular formation and migration, secreted less VEGF-A, and produced lower levels of phosphorylated AKT and ERK1/2 as well as active RAC1. CONCLUSION: Deletion of FLNA in ECs aggravated MI-induced LV dysfunction and cardiac failure as a result of defective endothelial response and increased scar formation by impaired endothelial function and signalling.
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Bandaru et al. (2014) studied Myocardial infarction. Endothelial deletion of FLNA vs. Flna(o/fl) control mice was evaluated on Post-MI remodelling of the left ventricle. Endothelial deletion of FLNA in mice aggravated MI-induced left ventricular dysfunction and cardiac failure due to defective endothelial response and increased scar formation.
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