Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme.

Certain matrix metalloproteinases (MMP) are expressed within the fibrous areas surrounding acellular lipid cores of atherosclerotic plaques, suggesting that these proteinases degrade matrix proteins within these areas and weaken the structural integrity of the lesion. We report that matrilysin and macrophage metalloelastase, two broad-acting MMPs, were expressed in human atherosclerotic lesions in carotid endarterectomy samples (n = 18) but were not expressed in normal arteries (n = 7). In situ hybridization and immunohistochemistry revealed prominent expression of matrilysin in cells confined to the border between acellular lipid cores and overlying fibrous areas, a distribution distinct from other MMPs found in similar lesions. Metalloelastase was expressed in these same border areas. Matrilysin was present in lipid-laden macrophages, identified by staining with anti-CD-68 antibody. Furthermore, endarterectomy tissue in organ culture released matrilysin. Staining for versican demonstrated that this vascular proteoglycan was present at sites of matrilysin expression. Biochemical studies showed that matrilysin degraded versican much more efficiently than other MMPs present in atherosclerotic lesions. Our findings suggest that matrilysin, specifically expressed in atherosclerotic lesions, could cleave structural proteoglycans and other matrix components, potentially leading to separation of caps and shoulders from lipid cores.

Reinnervation of the transplanted human heart as evidenced from heart rate variability studies.

This study evaluated heart rate variability (HRV) after cardiac transplantation in humans in an attempt to test the hypothesis that cardiac reinnervation occurs in the post-transplant period. HRV was measured using 24-hour Holter recordings performed on 37 ambulant patients 1 to 122 months after cardiac transplantation. All patients were free of histologic rejection and were taking no medication likely to influence HRV. Time and frequency domain were analyzed and circadian rhythm of hourly average heart rate was calculated. HRV increased with time after the transplant. Compared with patients in the early post-transplant period, patients > 36 months after transplant had lower 24-hour heart rates (86 vs 93 beats/min), an increased average of all 5-minute SDs of NN intervals (17.6 vs 11.3), and higher low-and high-frequency power. Ten of the 27 patients > 3 years after transplantation had evidence of functional cardiac reinnervation. Compared with patients who had no reinnervation, these patients had increased circadian variability with lower nocturnal heart rates (76 vs 91 beats/min) and greater sympathetic activity during daytime (natural logarithm sympathetic power -0.36 vs -1.45) and nighttime (natural logarithm sympathetic power -0.43 vs -1.98). Despite lower nocturnal heart rates, there was no HRV evidence for an increase in parasympathetic activity. Thus, patients late after cardiac transplantation have HRV evidence for an increase in sympathetic control of the heart.

Osteopontin expression is increased in the heritable cardiomyopathy of Syrian hamsters.

BACKGROUND: Osteopontin, a noncollagenous matrix protein, is transiently expressed in the heart after experimental cardiac injury, but its expression in states of continuing cardiac remodeling is unknown. We evaluated osteopontin expression in the heritable cardiomyopathy of the Syrian hamster. METHODS AND RESULTS: Hamster hearts were obtained for RNA isolation and analysis and in situ hybridization from two groups: normal control animals (n = 4) and untreated cardiomyopathic hamsters (n = 5). Osteopontin mRNA was 12-fold greater in cardiomyopathic hearts compared with normal controls (1.76 +/- 0.31 versus 0.14 +/- 0.04 arbitrary units normalized to GAPDH, mean +/- SEM, P < .05). In situ hybridization was used to define the origin of osteopontin in the heart. Osteopontin mRNA above background levels was not detected in sections from noncardiomyopathic hamster hearts but was readily detected in sections from cardiomyopathic hamsters, in which it originated in cells morphologically consistent with tissue macrophages. CONCLUSIONS: In the hamster, osteopontin is expressed in heritably cardiomyopathic hearts under conditions of chronic injury and repair, and the source of ostopontin message appears to be issue macrophage-like cells in foci of inflammation. This model could be used to evaluate the biological role of osteopontin in myocardial inflammation and remodeling.