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.
Highlights
Cardiac hypertrophy can result from increased hemodynamic load, myocardial infarction, extreme athletic training, aging, chronic respiratory diseases or can be seemingly idiopathic
Decreased expression of Foxm1 mRNA (Figure 1J) as well as less FOXM1-positive cardiomyocytes was observed in aMHC-Cre/Foxm1fl/fl hearts at P7 when compared to age-matched controls (Figure 1C & H)
We have previously shown that Foxm1 is a critical mediator of heart development and cardiomyocyte proliferation
Summary
Cardiac hypertrophy can result from increased hemodynamic load, myocardial infarction, extreme athletic training, aging, chronic respiratory diseases or can be seemingly idiopathic. Cardiac remodeling is only compensatory in the short term and leads to heart failure when either the chamber walls become too thin and weak to effectively expel blood (systolic dysfunction) or when thickening of the myocardium decreases the lumen of the chamber to the point the heart can no longer fill properly (diastolic dysfunction). Both outcomes are irreversible and require surgical intervention. Idiopathic cardiac hypertrophy typically manifests from a genetic predisposition and is known as hypertrophic cardiomyopathy. In many cases HCM is discovered by electrocardiography for another indication, with echocardiography remaining the best means to evaluate the extent and track the progression of HCM [2]
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