CARDIAC COLLAGEN REMODELING IN THE CARDIOMYOPATHIC SYRIAN-HAMSTER ANDTHE EFFECT OF LOSARTAN

Although increased deposition of collagen proteins has been described in cardiomyopathy, little is known of the temporal relationship betwee n events in collagen gene transcription and the occurrence of cardiac fibrosis, the removal of collagen by matrix metalloproteinases (MMPs), or of the regulation of these events by angiotensin AT(1) receptors i n this disease, We sought to study steady-state collagen mRNA abundanc e and the deposition of specific collagen subtypes in right and left v entricular muscle of Syrian cardiomyopathic (CMP) hamsters at differen t stages of cardiomyopathy. Using zymography, we also investigated the gelatinolytic activities of different MMPs to gain some information a bout collagen removal in experimental hearts. Finally, we investigated the effect of AT(1) receptor blockade (losartan) on collagen remodeli ng. Mie observed that the mRNA levels of types I and III collagens wer e significantly increased in all four experimental groups (35, 65, 120 , and 200 day) in left Ventricular tissue when compared to control (F1 -beta strain) values, The mRNA levels of these collagen species in exp erimental right Ventricular tissue samples were only elevated signific antly in the 35 and 200 day experimental groups when compared to contr ols. Fibrillar collagen deposition was elevated in left and right vent ricular CMP samples after a lag period from the occurrence of correspo nding increases in mRNA abundance. Although 2-week losartan treatment of 65, 120 and 200 day experimental groups had no significant effect o n left ventricular fibrillar collagen concentration or collagen mRNA a bundance when compared to vehicle-infused CMP hamsters, AT(1) receptor blockade was associated with complete regression of cardiac hypertrop hy Both MMP-1 (54 kDa band) and MMP-2 (58 and 62 kDa bands) activities were increased in left ventricular CMP tissues at 65, 120 and 200 day s when compared to F1-beta controls. Losartan treatment was associated with significant attenuation of MMP activities in cardiomyopathic sam ples at 65 and 120 days. Thus, elevation of mRNA abundance of fibrilla r collagen genes occurs at very early stages in this model of cardiomy opathy, and corresponding collagen proteins were subsequently deposite d in the cardiac interstitium at later stages. As collagen concentrati on was significantly increased in later stages of cardiomyopathy studi ed herein (120 and 200 day groups), our data support the hypothesis th at collagen synthesis exceeds the capacity of collagen removal during the progression of cardiomyopathy, Nevertheless, cardiac collagen remo deling may be facilitated by elevated MMP activity in cardiomyopathic stages in this experimental model, and we suggested that attenuation o f MMP activity in the presence of losartan may be a cardioprotective m echanism of this agent. (C) 1997 Academic Press Limited.