Caspases from apoptotic myocytes degrade extracellular matrix: a novel remodeling paradigm.
Induction of smooth muscle cell apoptosis is critical to the reversal of severe structural remodeling in hypertensive pulmonary arteries during disease regression. This process involves coordinated resorption of pathologically deposited extracellular matrix, including elastin, and occurs in the presence of serine elastase and matrix metalloproteinase inhibitors. Here, we show that apoptotic smooth muscle cells exhibit extensive degradation of elastin coincident with cell surface immunolocalization and release of caspases. We further document that recombinant caspase-2, -3, and -7 are potently elastolytic. These enzymes are present in an active form on apoptotic cell surfaces and caspase inhibitors attenuate their elastolytic activity. Our results reveal a previously undescribed function for apoptotic cells and a novel paradigm whereby removal of cells is coordinated with degradation of excess extracellular matrix during remodeling in development and disease.
Cowan
Kyle Northcote
KN
Division of Cardiovascular Research, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Leung
Wesley C Y
WC
Mar
Christopher
C
Bhattacharjee
Rakesh
R
Zhu
Yonghong
Y
Rabinovitch
Marlene
M
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053143:Caspase 2; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D020782:Matrix Metalloproteinases / Q000737:chemistry; D008564:Membrane Potentials; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D032342:Muscle Cells / Q000166:cytology / Q000473:pathology*; D009130:Muscle, Smooth / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D010196:Pancreatic Elastase / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D012694:Serine / Q000737:chemistry; D013347:Subcellular Fractions
D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D012694:Serine; D004549:Elastin; D010196:Pancreatic Elastase; C505410:Casp3 protein, rat; D053143:Caspase 2; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D020782:Matrix Metalloproteinases