Yoko Onozawa

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

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.

Reinduction of T-Type Calcium Channels by Endothelin-1 in Failing Hearts In Vivo and in Adult Rat Ventricular Myocytes In Vitro

Background—In ventricular myocardium, the T-type Ca2+ current (ICa,T), which is temporarily observed during fetal and neonatal periods, has been shown to reappear in failing/remodeling hearts. However, its pathophysiological regulation has not been elucidated. Methods and Results—We utilized Dahl salt-sensitive (DS) rats with hypertension at the stage of concentric left ventricular (LV) hypertrophy (11 weeks old, LVH) and at the heart failure stage (16 to 18 weeks old, CHF). Some were treated with bosentan (100 mg/kg per day) during the period from LVH to CHF. In LVH, neither the presence of ICa,T (measured in the freshly isolated LV myocytes) nor an increase in &agr;-1G mRNA expression were detected. This condition was associated with increases in tissue angiotensin II (AII) but not with endothelin (ET)-1 peptides. In contrast, in CHF, when the tissue AII remained elevated and ET-1 de novo increased, ICa,T was recorded in most of the cells (−0.87±0.18 pA/pF at −30 mV, P <0.01 versus LVH). This was associated with a significant increase in the &agr;-1G mRNA level. The chronic bosentan treatment eliminated both the elevation of &agr;-1G mRNA level and ICa,T from the cells, whereas it did not affect the cell size and membrane capacitance. In addition, 48-hour exposure to ET-1 but not AII induced ICa,T in normal adult myocytes in culture from Sprague-Dawley rats. Conclusions—ICa,T channels reappear in failing but not in hypertrophied LV cardiomyocytes in a manner depending on the tissue ET-1 activation.

Elevation of matrix metalloproteinase-2 level in pericardial fluid is closely associated with left ventricular remodeling.

The left ventricular (LV) extracellular matrix participates in progressive LV remodeling that is strongly associated with morbidity and mortality in patients with heart failure. Matrix metalloproteinases (MMPs), an endogenous family of zinc-dependent enzymes, increase proteolytic activity in the extracellar spaces, leading to increased extracellular remodeling. 1,2 Several lines of evidence in experiment animals suggest that MMPs and tissue inhibitors of metalloproteinases (TIMPs) may play an important role in modulating LV remodeling. 3,4 In humans, however, little information is available regarding MMPs and TIMPs of cardiac origin in the presence or absence of LV remodeling in patients with ischemic heart disease. It is generally considered that pericardial fluid is not only an ultrafiltrate of plasma, but also a transudate from the cardiac interstitium. 5 Thus, the purposes of this study were: (1) to measure plasma and pericardial fluid levels of total MMP-1 and -2, active MMP-2, and TIMP-1 and -2 in patients with ischemic heart disease, and (2) to investigate their relations to LV volume and function to obtain clinical evidence that MMPs act as autocrine and/or paracrine factors in the process of LV remodeling.