Activation of matrix metalloproteinase dilates and decreases cardiac tensile strength

Previous studies demonstrated that transition from compensatory pressure ov erload hypertrophy to decompensatory volume overload heart failure is assoc iated with decreased cardiac tensile strength and activation of matrix meta lloproteinase (MMP) in spontaneously hypertensive rat (SHR). To test the hy pothesis that in the absence of nitric oxide activation of MMP during cardi ac failure causes disruption in the organization of extracellular matrix (E CM) and leads to decrease systolic and diastolic cardiac tensile strength, we employed SHR of 24-32 weeks, which demonstrates significant cardiac hype rtrophy and fibrosis. The normotensive Wistar rats (NWR) were used as contr ol. To determine whether cardiac hypertrophy is associated with increased e lastinolytic matrix metalloproteinase-2 (MMP-2) activity; quantitative elas tin-zymography was performed on cardiac tissue homogenates. The MMP-2 activ ity was normalized by the levels of actin. The MMP-2/actin ratio was 2.0 +/ -0.5 in left ventricle (LV) and 1.5 +/-0.25 in right ventricle (RV) of SHR3 2wks and 0.5 +/-0.25 in LV and 0.25 +/-0.12 in RV of NWR32wks, (P <0.02 whe n SHR compared with NWR). To measure passive diastolic cardiac function, ri ngs from LV as well as RV through transmyocardial wall from male SHR and NW R of 6-8 weeks and 24-36 weeks were prepared. The LV wall thickness from en docardium to epicardium was 3.75 +/-0.25 mm in SHR32wks, as compared to 2.2 5 +/-0.50 mm in NWR32wks (P <0.01). The ring was placed in tissue myobath a nd length-tension relationships were assessed. The pressure-length relation ship was shifted to left in SHR as compared to NWR. The amounts of cardiac elastin and collagen were determined spectrophotometrically by measuring de smosine-isodesmosine and hydroxyproline contents, respectively. A negative correlation between elastic tensile strength and elastin/collagen ratio was elucidated. To create situation analogous to heart failure and MMP activat ion, we treated cardiac rings with active MMP-2 and length-tension relation was measured. The relationship was shifted to right in both SHR and NWR wh en compared to their respective untreated groups. The results suggested tha t activation of MMP led to decreased cardiac tissue tensile strength and ma y cause systolic and diastolic dysfunction. (C) 2001 Elsevier Science Irela nd Ltd. All rights reserved.