EXPERIMENTAL STUDY
Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats
Yoshitaka Iwanaga, MD, PhD*,
Takeshi Aoyama, MD, PhD*,
Yasuki Kihara, MD, PhD, FACC*,*,
Yoko Onozawa, MD*,
Takeshi Yoneda, MD* and
Shigetake Sasayama, MD, PhD, FACC*
* 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.
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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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