Abstract
Pressure overload of the heart leads to cardiac remodeling that may progress into heart failure, a common, morbid and mortal condition. Increased mechanistic insight into remodeling is instrumental for development of novel heart failure treatment. Cardiac remodeling comprises cardiomyocyte hypertrophic growth, extracellular matrix alterations including fibrosis, and inflammation. Fibromodulin is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis. Fibromodulin is expressed in the cardiac extracellular matrix, however its role in the heart remains largely unknown. We investigated fibromodulin levels in myocardial biopsies from heart failure patients and mice, subjected fibromodulin knock-out (FMOD-KO) mice to pressure overload by aortic banding, and overexpressed fibromodulin in cultured cardiomyocytes and cardiac fibroblasts using adenovirus. Fibromodulin was 3-10-fold upregulated in hearts of heart failure patients and mice. Both cardiomyocytes and cardiac fibroblasts expressed fibromodulin, and its expression was increased by pro-inflammatory stimuli. Without stress, FMOD-KO mice showed no cardiac phenotype. Upon aortic banding, left ventricles of FMOD-KO mice developed mildly exacerbated hypertrophic remodeling compared to wild-type mice, with increased cardiomyocyte size and altered infiltration of leukocytes. There were no differences in mortality, left ventricle dilatation, dysfunction or expression of heart failure markers. Although collagen amount and cross-linking were comparable in FMOD-KO and wild-type, overexpression of fibromodulin in cardiac fibroblasts in vitro decreased their migratory capacity and expression of fibrosis-associated molecules, i.e. the collagen-cross linking enzyme lysyl oxidase, transglutaminase 2 and periostin. In conclusion, despite a robust fibromodulin upregulation in clinical and experimental heart failure, FMOD-KO mice showed a relatively mild hypertrophic phenotype. In cultured cardiac fibroblasts, fibromodulin has anti-fibrotic effects.
Highlights
Pressure overload of the heart, as seen in patients with hypertension or aortic stenosis, leads to cardiac remodeling and may progress into heart failure (HF) [1]
Fibromodulin is upregulated in clinical heart failure
The patients had an average Left ventricle (LV) ejection fraction of 19% and were classified in New York Heart Association classes III-IV (S3 Table). They had elevated circulating levels of pro- brain natriuretic peptide levels, and dilatation was evident from an average LV internal diameter in diastole (LVIDd) of 7.5 cm
Summary
Pressure overload of the heart, as seen in patients with hypertension or aortic stenosis, leads to cardiac remodeling and may progress into heart failure (HF) [1]. Increased mechanistic insight into cardiac remodeling and HF will likely contribute to development of novel HF treatment. Cardiac remodeling encompasses cardiomyocyte (CM) hypertrophic growth or death, and extracellular matrix (ECM) alterations such as increased levels of fibrillar collagens (i.e. fibrosis) and collagen cross-linking, fibroblast-to-myofibroblast transdifferentiation, and inflammation [3]. The ECM is increasingly recognized as an important mediator of cardiac remodeling [4,5,6,7,8]. Most proteoglycans are localized to, or extending into the ECM, and they are increasingly believed to play a role in cardiac remodeling [4, 5, 10,11,12]
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