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Inactivation of endothelial proprotein convertase 5/6 decreases collagen deposition in the cardiovascular system: role of fibroblast autophagy

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Abstract

Proprotein convertase (PC) 5/6 belongs to a family of secretory proteases involved in proprotein proteolysis. Several studies suggest a role for PC5/6 in cardiovascular disease. Because lethality at birth of mice lacking PC5/6 precluded elucidation of its function in the adult, we generated mice in which the gene of PC5/6 (pcsk5) is specifically inactivated in endothelial cells (ecKO), which are viable and do not exhibit overt abnormalities. In order to uncover the function of PC5/6 in the cardiovascular system, the effect of ecKO was studied in aging mice. In 16 to 18-month-old ecKO mice, the left ventricle (LV) mass, media cross-sectional area of aorta and coronary arteries, and media-to-lumen ratio of mesenteric arteries were decreased. The LV presented decreased diastolic function, and mesenteric arteries showed decreased stiffness. Collagen was decreased in the LV myocardial interstitium and perivascularly in coronary arteries and aorta. Cardiovascular hypotrophy likely develops with aging, since no significant changes were observed in 2-month-old ecKO mice. Fibroblasts, as a source of collagen in myocardium and vasculature, may play a role in the decrease in collagen deposition. Fibroblasts co-cultured with ecKO endothelial cells showed decreased collagen production, decreased insulin-like growth factor (IGF)-1/Akt/mTOR signaling, and enhanced autophagic activation. PC5/6 inactivation in endothelial cells results in cardiovascular hypotrophy associated with decreased collagen deposition, decreased LV diastolic function, and vascular stiffness, suggesting a trophic role of endothelial PC5/6 in the cardiovascular system, likely mediated by IGF-1/Akt/mTOR signaling and control of autophagy.

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Acknowledgments

We are grateful to Edwige Marcinkiewicz, Manon Laprise, André Turgeon, Marie-Eve Deschênes, and Claudia Toulouse for excellent technical support and animal care. AP and NGS were funded by Canadian Institutes of Health Research (CIHR) grant MOP44363 and team grant CTP82946 and NGS by a Canada Research Chair (CRC) from CIHR/Government of Canada # 216684. Work at the LDI was funded by CIHR grants MOP82790, a CRC on Hypertension and Vascular Research from CIHR/Government of Canada, and by the Canada Fund for Innovation, all to ELS.

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Authors and Affiliations

  1. Lady Davis Institute for Medical Research, Montreal, Quebec, Canada

    Chiara Marchesi, Catherine A. Lemarié, Eyal Leibovitz, Talin Ebrahimian, Pierre Paradis & Ernesto L. Schiffrin

  2. Department of Medicine, Sir Mortimer B. Davis–Jewish General Hospital, McGill University, #B-127, 3755 Cote Ste-Catherine Road, Montreal, Quebec, H3T 1E2, Canada

    Ernesto L. Schiffrin

  3. Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, University of Montreal, 110 Pine Avenue West, Montreal, Quebec, H2W 1R7, Canada

    Rachid Essalmani, Nabil G. Seidah & Annik Prat

  4. Department of Clinical Medicine, University of Insubria, Varese, Italy

    Chiara Marchesi

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  1. Chiara Marchesi
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  2. Rachid Essalmani
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  3. Catherine A. Lemarié
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  8. Ernesto L. Schiffrin
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  9. Annik Prat
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Corresponding authors

Correspondence to Ernesto L. Schiffrin or Annik Prat.

Additional information

C. Marchesi and R. Essalmani contributed equally to this work.

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Marchesi, C., Essalmani, R., Lemarié, C.A. et al. Inactivation of endothelial proprotein convertase 5/6 decreases collagen deposition in the cardiovascular system: role of fibroblast autophagy. J Mol Med 89, 1103–1111 (2011). https://doi.org/10.1007/s00109-011-0776-9

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  • DOI: https://doi.org/10.1007/s00109-011-0776-9

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