CELLULAR-LOCALIZATION AND REGIONAL DISTRIBUTION OF AN ANGIOTENSIN-II FORMING CHYMASE IN THE HEART

The human heart is a target organ for the octapeptide hormone, angiote nsin II (Ang II). Recent studies suggest that the human heart contains a dual pathway of Ang II formation in which the major Ang II-forming enzymes are angiotensin I-converting enzyme (ACE) and chymase. Human h eart chymase has recently been purified and its CDNA and gene cloned. This cardiac serine proteinase is the most efficient and specific Ang II-forming enzyme described. To obtain insights into the cardiac sites of chymase-dependent Ang II formation, we examined the cellular local ization and regional distribution of chymase in the human heart. Elect ron microscope immunocytochemistry using an anti-human chymase antibod y showed the presence of chymase-like immunoreactivity in the cardiac interstitium and in cytosolic granules of mast cells, endothelial cell s, and some mesenchymal interstitial cells. In the cardiac interstitiu m, chymase-like immunoreactivity is associated with the extracellular matrix. In situ hybridization studies further indicated that chymase m RNA is expressed in endothelial cells and in interstitial cells, inclu ding mast cells. Tissue chymase levels were determined by activity ass ays and by Western blot analyses. Chymase levels were approximately tw ofold higher in ventricles than in atria. There were no significant di fferences in chymase levels in ventricular tissues obtained from nonfa iling donor hearts, failing ischemic hearts, or hearts from patients w ith ischemic cardiomyopathy. These findings suggest that a major site of chymase-dependent Ang II formation in the heart is the interstitium and that cardiac mast cells, mesenchymal interstitial cells, and endo thelial cells are the cellular sites of synthesis and storage of chyma se. In the human heart, because ACE levels are highest in the atria an d chymase levels are highest in ventricles, it is likely that the rela tive contribution of ACE and chymase to cardiac Ang II formation varie s with the cardiac chamber. Such differences may lead to differential suppression of cardiac Ang II levels during chronic ACE inhibitor ther apy in patients with congestive heart failure.