Regulation of extracellular matrix proteins in pressure-overload cardiac hypertrophy: effects of angiotensin converting enzyme inhibition.
OBJECTIVE
Left ventricular hypertrophy (LVH) is characterized by remodeling of both myocyte and interstitial compartments of the heart. The aim of this investigation was to study the effects of angiotensin converting enzyme (ACE) inhibition on alterations in the composition of the interstitium in chronic pressure-overload hypertrophy.


METHODS
LVH was induced in weanling rats by banding the ascending aorta. Animals with aortic banding received either vehicle (n = 20), hydralazine (20 mg/kg per day, n = 20), or the ACE inhibitor ramipril (10 mg/kg per day, n = 20) during weeks 6-12 after banding.


RESULTS
Compared with sham-operated, untreated rats (n = 20), aortic-banded vehicle and hydralazine-treated rats displayed substantially increased left ventricular weights and myocyte diameters whereas ramipril significantly blunted the hypertrophic response at the myocyte level (each P < 0.001) as well as the increase in left ventricular weight (each P < 0.01). In addition, image analysis revealed a significant induction of perivascular and interstitial tissue accumulation in vehicle- and hydralazine-treated rats (2.5-fold, each P < 0.0001). In contrast, ramipril-treated rats displayed attenuated interstitial and perivascular fibrosis, both being significantly diminished compared with vehicle- and hydralazine-treated rats (each P< 0.001). Further, vehicle- and hydralazine-treated rats were characterized by elevated steady-state messenger (m)RNA levels of fibronectin (2.7- and 2.8-fold, P< 0.005), collagen I (2.0- and 1.8-fold, P < 0.0005), collagen III (both 2.2-fold, P < 0.001) and laminin B (1.6- and 1.6-fold, P < 0.005). In parallel, the corresponding immunohistochemical signals were markedly enhanced in these groups. In comparison, ramipril significantly blunted the induction of collagen I and III, laminin B and fibronectin at both the mRNA and protein levels. These morphological and molecular differences between the hydralazine and ramipril groups could not be attributed to differences in left ventricular-pressures, which were markedly elevated in all aortic stenosis rats (1.9-fold, each P < 0.001 versus sham). In fact, given that ramipril but not hydralazine blunted the hypertrophic response to pressure overload, the echocardiographic measurements revealed that left ventricular systolic wall stress was higher in the ramipril group (70 +/- 1 versus 34 +/- 0.7 kdyn/cm2; P < 0.02).


CONCLUSIONS
ACE inhibition may limit both myocyte and interstitial remodeling despite ongoing cardiac pressure overload.
Grimm
D
D
Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Germany.
Kromer
E P
EP
Böcker
W
W
Bruckschlegel
G
G
Holmer
S R
SR
Riegger
G A
GA
Schunkert
H
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000150:complications*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D007797:Laminin / Q000378:metabolism; D008297:Male; D011347:Procollagen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000235:genetics
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D007797:Laminin; D011347:Procollagen; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D006830:Hydralazine; D017257:Ramipril