Petri Kovanen

Association Between Complement Factor H and Proteoglycans in Early Human Coronary Atherosclerotic Lesions: Implications for Local Regulation of Complement Activation

Objective—Complement activation has been suggested to play a role in atherogenesis. To study the regulation of complement activation in human coronary atherosclerotic lesions, we examined the spatial relationships between the major complement inhibitor, factor H, and the complement activation products C3d and C5b-9. Methods and Results—In early lesions (American Heart Association types II and III), factor H was immunohistochemically found in the superficial proteoglycan-rich layer in association with numerous macrophages and C3d, whereas C5b-9 was found deeper in the intima, where factor H was virtually absent. In vitro experiments involving surface plasmon resonance and affinity chromatography analyses demonstrated that isolated human arterial proteoglycans bind factor H, and functional complement assays showed that glycosaminoglycans inhibit the complement activation induced by modified low density lipoprotein or by a foreign surface. Conclusions—The present observations raise the possibility that proteoglycans, because of their ability to bind the major complement inhibitor factor H, may inhibit complement activation in the superficial layer of the arterial intima. In contrast, deeper in the intima, where factor H and proteoglycans are absent, complement may be activated and proceed to C5b-9. Thus, the superficial and the deep layers of the human coronary artery appear to differ in their ability to regulate complement activation.

Role For Chymase in Heart Failure Angiotensin II-Dependent or -Independent Mechanisms?

One of the major questions regarding the role of angiotensin II (Ang II) in the pathophysiology of heart failure has been whether other enzymes, in addition to angiotensin-converting enzyme (ACE), could contribute to the local production of Ang II in the heart. Specifically, there is controversy as to whether the major Ang II-forming enzyme within the heart is ACE or chymase, a chymotrypsin-like serine protease that is synthesized and stored in the cardiac mast cells and is not affected by ACE inhibitors. See p 2555 Formation of Ang II in the heart has been studied both in vitro and in vivo, but the results of these experiments are inconsistent. In vitro experiments with human1,2 or animal heart extracts,3,4 derived from either normal or failing hearts, have demonstrated unequivocally that the major Ang II-forming enzyme, responsible for 80% to 90% of the Ang II-forming capacity in the heart extracts, is chymase. In striking contrast, experiments in vivo with normal5,6 or failing dog hearts7,8 have demonstrated that most (>70%) of the Ang II formation can be inhibited by an ACE inhibitor, indicating that, under these conditions, the major Ang II-forming enzyme is ACE. Moreover, in normal human hearts, Zisman et al9 have demonstrated that, in vivo, the major Ang II-forming enzyme is ACE, as 90% of the Ang II formation could be inhibited by an ACE inhibitor. However, no experiments with intact failing human hearts have been performed. The obvious explanation for the discrepancy between the in vitro and in vivo studies is that the chymase-mediated Ang II formation is subjected to local regulation, a fact that has been overlooked in the studies performed in vitro. Thus, chymase activity is known to be regulated by at least 2 factors: Those that lead to stimulation and degranulation of …