Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease.
In a rat model of pulmonary hypertension induced by monocrotaline, medial hypertrophy of the pulmonary arteries is associated with enhanced production (synthesis) of insoluble elastin relative to accumulation and an increased number of elastin fragments, features suggestive of an elastolytic process. In the present study, we measured and characterized pulmonary artery (PA) elastolytic activity at time points before as well as coincident with the progression of medial hypertrophy in monocrotaline-injected adult male Sprague-Dawley rats. We also determined whether medial hypertrophy is preceded by ultrastructural changes in elastin. Since medial hypertrophy develops but fails to progress in rats injected with monocrotaline at 8 days of age, we assessed whether, compared with adult rats, there were also structural and biochemical differences in elastin and elastolytic activity. A twofold increase in elastolytic activity per milligram tissue was observed 2 days after monocrotaline injection in adult rats (p less than 0.01), and there was an increased number of breaks in the internal elastic lamina (IEL) at 4 days (p less than 0.05) (i.e., before the development of medial hypertrophy). Associated with the progression of medial hypertrophy between 16 and 28 days after monocrotaline injection, there was a further threefold increase in elastolytic activity per milligram tissue by 28 days (p less than 0.01). Susceptibility of the elastolytic activity to specific inhibitors suggested that one or more serine elastases is involved. In infant rats in which medial and right ventricular hypertrophy fail to progress in severity between 16 and 28 days after monocrotaline injection, we did not measure an increase in elastolytic activity, nor was there evidence of an increase in the number of breaks in the IEL at 4 days, suggesting a lack of increased elastolytic activity at an earlier time point. The total content of PA elastin in infant rats, although increased compared with control rats (p less than 0.01), was not associated with heightened production and appeared ultrastructurally as thicker laminae (p less than 0.05) rather than as fragments previously reported in adult rats.
Todorovich-Hunter
L
L
Department of Pediatrics, University of Toronto, Ontario, Canada.
Dodo
H
H
Ye
C
C
McCready
L
L
Keeley
F W
FW
Rabinovitch
M
M
D000367:Age Factors; D000818:Animals; D003094:Collagen / Q000096:biosynthesis; D004549:Elastin / Q000096:biosynthesis; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006984:Hypertrophy; D008297:Male; D016686:Monocrotaline; D010196:Pancreatic Elastase / Q000378:metabolism*; D011651:Pulmonary Artery / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains
D016686:Monocrotaline; D003094:Collagen; D004549:Elastin; D010196:Pancreatic Elastase