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- W2980454296 abstract "Cardiac hypertrophy is a well-known risk factor for heart failure. Cardiomyocytes are often considered the ultimate culprit of cardiac remodeling following stress, despite comprising less than half of the heart’s total cells. Recent work has begun to recognize the importance of non-myocyte populations in the heart, yet how signaling between these and cardiomyocytes can dictate cardiac remodeling is still largely unknown. We have found that Microfibrillar-associated protein 4 (MFAP4) is a novel mediator of intercellular communication in the heart, and is specifically required for cardiac adaptation to stress. MFAP4 is an extracellular matrix protein that has been previously shown as a necessary component of arterial remodeling following injury, but its role in cardiac hypertrophy has not been explored. Our data revealed that, in the heart, MFAP4 is selectively secreted by vascular smooth muscle cells and endothelial cells in response to transforming growth factor β (TGFβ) activation. To determine the role of MFAP4 in cardiac hypertrophy, we subjected MFAP4-deficient mice to two forms of stress: chronic pressure overload or 1 week administration of the pro-fibrotic agent Angiotensin II (AngII). MFAP4-deficient mice developed accelerated cardiac hypertrophy, fibrotic remodeling, and marked cardiac functional defects with pressure overload when compared to wild-type animals. Also, AngII administration was sufficient to exacerbate cardiac hypertrophy prior to marked cardiac functional decline in MFAP4-deficient mice, suggesting a primary role for MFAP4 in regulating cardiomyocyte growth. Furthermore, aging-induced cardiac stress led to left ventricular dilation and spontaneous development of functional defects in otherwise unstressed MFAP4-deficient mice. Mechanistically, MFAP4 possess an integrin-binding domain and can affect cardiac homeostasis downstream of cardiomyocyte integrins via altered signaling through the FAK-ERK cascade, well-known to dictate cardiomyocyte geometric remodeling. Overall, our study demonstrates a critical role for MFAP4 on cardiac hypertrophy and function post-injury, underscoring the importance of non-myocyte-derived factors on cardiomyocyte pathophysiology." @default.
- W2980454296 created "2019-10-25" @default.
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- W2980454296 date "2019-08-02" @default.
- W2980454296 modified "2023-09-27" @default.
- W2980454296 title "Abstract 248: Microfibrillar-Associated Protein 4 Regulates Maladaptive Cardiac Remodeling" @default.
- W2980454296 doi "https://doi.org/10.1161/res.125.suppl_1.248" @default.
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