Back to Search
Start Over
Inactivation of endothelial proprotein convertase 5/6 decreases collagen deposition in the cardiovascular system: role of fibroblast autophagy.
- Source :
-
Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2011 Nov; Vol. 89 (11), pp. 1103-11. Date of Electronic Publication: 2011 Jun 17. - Publication Year :
- 2011
-
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.
- Subjects :
- Animals
Collagen genetics
Coronary Vessels pathology
Endothelial Cells pathology
Fibroblasts pathology
Humans
Insulin-Like Growth Factor I genetics
Insulin-Like Growth Factor I metabolism
Mice
Mice, Transgenic
Myocardium metabolism
Myocardium pathology
Organ Size genetics
Proprotein Convertase 5 genetics
Proteolysis
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction genetics
TOR Serine-Threonine Kinases genetics
TOR Serine-Threonine Kinases metabolism
Autophagy
Collagen biosynthesis
Coronary Vessels metabolism
Endothelial Cells enzymology
Fibroblasts enzymology
Proprotein Convertase 5 metabolism
Vascular Stiffness
Subjects
Details
- Language :
- English
- ISSN :
- 1432-1440
- Volume :
- 89
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of molecular medicine (Berlin, Germany)
- Publication Type :
- Academic Journal
- Accession number :
- 21681612
- Full Text :
- https://doi.org/10.1007/s00109-011-0776-9