Postnatal Ablation of Foxm1 from Cardiomyocytes Causes Late Onset Cardiac Hypertrophy and Fibrosis without Exacerbating Pressure Overload-Induced Cardiac Remodeling

Abstract

Heart disease remains a leading cause of morbidity and mortality in the industrialized world. Hypertrophic cardiomyopathy is the most common genetic cardiovascular disorder and the most common cause of sudden cardiac death. Foxm1 transcription factor (also known as HFH-11B, Trident, Win or MPP2) plays an important role in the pathogenesis of various cancers and is a critical mediator of post-injury repair in multiple organs. Foxm1 has been previously shown to be essential for heart development and proliferation of embryonic cardiomyocytes. However, the role of Foxm1 in postnatal heart development and in cardiac injury has not been evaluated. To delete Foxm1 in postnatal cardiomyocytes, αMHC-Cre/Foxm1fl/fl mice were generated. Surprisingly, αMHC-Cre/Foxm1fl/fl mice exhibited normal cardiomyocyte proliferation at postnatal day seven and had no defects in cardiac structure or function but developed cardiac hypertrophy and fibrosis late in life. The development of cardiomyocyte hypertrophy and cardiac fibrosis in aged Foxm1-deficient mice was associated with reduced expression of Hey2, an important regulator of cardiac homeostasis, and increased expression of genes critical for cardiac remodeling, including MMP9, αSMA, fibronectin and vimentin. We also found that following aortic constriction Foxm1 mRNA and protein were induced in cardiomyocytes. However, Foxm1 deletion did not exacerbate cardiac hypertrophy or fibrosis following chronic pressure overload. Our results demonstrate that Foxm1 regulates genes critical for age-induced cardiomyocyte hypertrophy and cardiac fibrosis.

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

“…This includes binding sites for transcription factors such as ATF2, FOXM1, STAT3, and MEF2A (Fig. 1B), which are reported to have roles in cardiac function either independently (16,17) or in cross-talk with the endothelin system (18,19). Also, within this cluster, the strongest signal was a 400-bp Chip-seq peak for the FOS/JUN (chr13:78503006-78503405; Fig.…”

“…Although none of the SNPs were in the coding regions, many of these SNPs were overlying a cluster of transcription-factor binding sites identified in ENCODE ( Fig. 1 A and B), where the underlying transcription factors were reported to have roles in endothelin-mediated cardiac function (16,18,19). Promoter luciferase assay of the EDNRB gene indicated an 89-fold increased activity with an intact 1,258-bp promoter sequence and a further boost of 2.7-and 3.1-fold with overexpression of c-Jun or C/EBPb, respectively (21).…”

FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis

“…Its postnatal deletion from cardiomyocytes led to cardiac fibrosis (36), while on the other hand, its deletion from alveolar epithelial cells protected against radiationinduced pulmonary fibrosis and epithelial-mesenchymal transition (EMT) (37). Recent studies using lineage tracing to explore the origins of myofibroblasts -the ultimate effectors of tissue fibrosis -in models of lung fibrosis have concluded that an in vivo role for EMT is either absent or minimal (38)(39)(40) and instead emphasize the importance of resident lung fibroblasts as their major source (39,40).…”

β‐catenin and Kras/Foxm1 signaling pathway are critical to restrict Sox9 in basal cells during pulmonary branching morphogenesis

“…Expression of an activated Kras G12D in respiratory epithelial cells impaired branching lung morphogenesis, increased MAPK activity and induced expression of Sprouty-2, a Ras/ERK antagonist (Shaw et al, 2007). Foxm1 transcription factor is a key downstream target of the Kras/ERK signaling pathway and an important regulator of cellular proliferation during embryonic development, organ injury and carcinogenesis (Bolte et al, 2011(Bolte et al, , 2012Balli et al, 2012;Sengupta et al, 2013;Cheng et al, 2014;Xia et al, 2015). Kras downstream kinases, including ERK, Cdk1, and Cdk2, directly phosphorylate Foxm1 and induce its transcriptional activity (Major et al, 2004;Ma et al, 2005).…”