Collagenase‐resistant collagen promotes mouse aging and vascular cell senescence

Aging Cell

Faran Vafaie²  Hao Yin²  Caroline O'Neil²  Zengxuan Nong²  Alanna Watson²  John-Michael Arpino²  Michael W. A. Chu¹  David Wayne Holdsworth²  Robert Gros² 

[1] Department of Surgery, Western University, London, ON, Canada;Robarts Research Institute, Western University, London, ON, Canada

关键词: collagen;    integrin;    senescence;    vascular smooth muscle;   

DOI  :  10.1111/acel.12155

来源: Wiley

【 摘 要 】

Summary

Collagen fibrils become resistant to cleavage over time. We hypothesized that resistance to type I collagen proteolysis not only marks biological aging but also drives it. To test this, we followed mice with a targeted mutation (Col1a1^r/r) that yields collagenase-resistant type I collagen. Compared with wild-type littermates, Col1a1^r/r mice had a shortened lifespan and developed features of premature aging including kyphosis, weight loss, decreased bone mineral density, and hypertension. We also found that vascular smooth muscle cells (SMCs) in the aortic wall of Col1a1^r/r mice were susceptible to stress-induced senescence, displaying senescence-associated ß-galactosidase (SA-ßGal) activity and upregulated p16^INK4A in response to angiotensin II infusion. To elucidate the basis of this pro-aging effect, vascular SMCs from twelve patients undergoing coronary artery bypass surgery were cultured on collagen derived from Col1a1^r/r or wild-type mice. This revealed that mutant collagen directly reduced replicative lifespan and increased stress-induced SA-ßGal activity, p16^INK4A expression, and p21^CIP1 expression. The pro-senescence effect of mutant collagen was blocked by vitronectin, a ligand for αvß3 integrin that is presented by denatured but not native collagen. Moreover, inhibition of αvß3 with echistatin or with αvß3-blocking antibody increased senescence of SMCs on wild-type collagen. These findings reveal a novel aging cascade whereby resistance to collagen cleavage accelerates cellular aging. This interplay between extracellular and cellular compartments could hasten mammalian aging and the progression of aging-related diseases.

【 授权许可】

CC BY   
© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.