Bilsen, M. (Marc) van

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2017 - 20202

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    Cartilage intermediate layer protein 1 (CILP1): a novel mediator of cardiac extracellular matrix remodelling
    (2017) Veld, R.C. (Roel C.) op't; Nieuwenhoven, F.A. (Frans A.) van; Diez-Martinez, J. (Javier); Heymans, S. (Stephane); Munts, C. (Chantal); Schroen, B. (Blanche); Bilsen, M. (Marc) van; González-Miqueo, A. (Aránzazu)
    Heart failure is accompanied by extracellular matrix (ECM) remodelling, often leading to cardiac fibrosis. In the present study we explored the significance of cartilage intermediate layer protein 1 (CILP1) as a novel mediator of cardiac ECM remodelling. Whole genome transcriptional analysis of human cardiac tissue samples revealed a strong association of CILP1 with many structural (e.g. COL1A2 r2¿=¿0.83) and non-structural (e.g. TGFB3 r2¿=¿0.75) ECM proteins. Gene enrichment analysis further underscored the involvement of CILP1 in human cardiac ECM remodelling and TGFß signalling. Myocardial CILP1 protein levels were significantly elevated in human infarct tissue and in aortic valve stenosis patients. CILP1 mRNA levels markedly increased in mouse heart after myocardial infarction, transverse aortic constriction, and angiotensin II treatment. Cardiac fibroblasts were found to be the primary source of cardiac CILP1 expression. Recombinant CILP1 inhibited TGFß-induced ¿SMA gene and protein expression in cardiac fibroblasts. In addition, CILP1 overexpression in HEK293 cells strongly (5-fold p¿<¿0.05) inhibited TGFß signalling activity. In conclusion, our study identifies CILP1 as a new cardiac matricellular protein interfering with pro-fibrotic TGFß signalling, and as a novel sensitive marker for cardiac fibrosis.
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    Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities
    (Springer, 2020) Jones, E.A.V. (Elizabeth A. V.); Czarnowska, E. (Elzbieta); Simmonds, S. (Steven J.); Ratajska, A. (Anna); Mulder, P. (Paul); Heymans, S. (Stephane); Kuhn, A.R. (Annika R.); Bilsen, M. (Marc) van; González-Miqueo, A. (Aránzazu); Cuijpers, I. (Ilona); Brakenhielm, E. (Ebba)
    Heart failure with preserved ejection fraction (HFpEF) is a complex heterogeneous disease for which our pathophysiological understanding is still limited and specifc prevention and treatment strategies are lacking. HFpEF is characterised by diastolic dysfunction and cardiac remodelling (fbrosis, infammation, and hypertrophy). Recently, microvascular dysfunction and chronic low-grade infammation have been proposed to participate in HFpEF development. Furthermore, several recent studies demonstrated the occurrence of generalized lymphatic dysfunction in experimental models of risk factors for HFpEF, including obesity, hypercholesterolaemia, type 2 diabetes mellitus (T2DM), hypertension, and aging. Here, we review the evidence for a combined role of coronary (micro)vascular dysfunction and lymphatic vessel alterations in mediating key pathological steps in HFpEF, including reduced cardiac perfusion, chronic low-grade infammation, and myocardial oedema, and their impact on cardiac metabolic alterations (oxygen and nutrient supply/demand imbalance), fbrosis, and cardiomyocyte stifness. We focus primarily on HFpEF caused by metabolic risk factors, such as obesity, T2DM, hypertension, and aging.