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EXPERIMENTAL STUDY

Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats

^* Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

Manuscript received June 2, 2000; revised manuscript received January 7, 2002, accepted January 28, 2002.

^* Reprint requests and correspondence: Dr. Yasuki Kihara, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto Japan
kihara{at}kuhp.kyoto-u.ac.jp

OBJECTIVES: We sought to elucidate how the local activation of matrix metalloproteinases (MMPs) is balanced by that of the endogenous tissue inhibitors of MMP (TIMPs) during left ventricular (LV) remodeling.

BACKGROUND: Although it is known that the extracellular matrix (ECM) must be altered during LV remodeling, its local regulation has not been fully elucidated.

METHODS: In Dahl salt-sensitive rats with hypertension, in which a stage of concentric, compensated left ventricular hypertrophy (LVH) at 11 weeks is followed by a distinct stage of congestive heart failure (CHF) with LV enlargement and dysfunction at 17 weeks, we determined protein and messenger ribonucleic acid (mRNA) levels of LV myocardial TIMP-2 and -4 and MMP-2, as well as their concomitant activities.

RESULTS: No changes were found at the LVH stage. However, during the transition to CHF, TIMP-2 and -4 activities, protein and mRNA levels were all sharply increased. At the same time, the MMP-2 mRNA and protein levels and activities, as determined by gelatin zymography, as well as by an antibody capture assay, showed a substantial increase during the transition to CHF. The net MMP activities were closely related to increases in LV diameter (r = 0.763) and to systolic wall stress (r = 0.858) in vivo.

CONCLUSIONS: Both TIMPs and MMP-2 remained inactive during hypertrophy, per se; they were activated during the transition to CHF. At this time, the activation of MMP-2 surpassed that of TIMPs, possibly resulting in ECM breakdown and progression of LV enlargement.

Abbreviations and Acronyms   bp   base pair   cDNA   complementary deoxyribonucleic acid   CHF   congestive heart failure   DR   Dahl salt-resistant   DS   Dahl salt-sensitive   ECM   extracellular matrix   GAPDH   glyceraldehyde-3-phosphate dehydrogenase   LV   left ventricular   LVH   left ventricular hypertrophy   MMP   matrix metalloproteinase   mRNA   messenger ribonucleic acid   RT-PCR   reverse transcriptase-polymerase chain reaction   TIMP   tissue inhibitor of matrix metalloproteinase

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