A Novel Aspect of Endothelium Dysfunction

The renin-angiotensin and cardiac natriuretic systems play an important role in the pathophysiology of congestive heart failure (CHF). The status of the membrane-bound pulmonary and renal activities of three ectoenzymes involved in the regulation of these systems angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP), and aminopeptidase A (APA) -was investigated in Wistar rats 3 months after induction of myocardial infarction (MI) and in shamoperated (control) rats. Plasma renin activity and ACE activity, plasma angiotensin II (Ang II) levels, and atrial natriuretic factor levels were simultaneously determined. The lung ACE activity was decreased in MI rats compared with control rats (P<.0001), and this decrease depended on the severity of the heart failure. In contrast, plasma ACE activity was increased in MI rats (P<.01), and this increase was also proportional to the severity of MI. Northern blot analysis showed that the lung ACE mRNA level in severe MI rats was half that of the control rats. Renal ACE activity of the MI rats was not affected, and ongestive heart failure (CHF) is a syndrome in C which the heart is unable to deliver nutrient blood to peripheral tissues at normal levels of ventricular filling pressure. The syndrome is most often caused by impaired left ventricular performance and, particularly in severe or decompensated CHF, is accompanied by complex abnormalities of the peripheral circulation.' Activation of the renin-angiotensin system is claimed to occur in CHF.23 Plasma renin activity and renal renin content are known to increase in clinical and experimental myocardial infarction (MI).2,3 Plasma angiotensinogen is decreased in patients with severe heart failure.4 Despite the importance of the renin-angiotensin system in the pathogenesis of CHF, relatively little is known about the status of the enzymes that can modify the activity of the effector hormone, angiotensin II (Ang IL), in this setting. Angiotensin-converting enzyme (ACE, EC 3.4.15.1) plays an important role in the regulation of the reninangiotensin system by converting angiotensin I (Ang I) into Ang 11.5,6 This enzyme is a membrane-bound zinc metalloprotease predominantly present at the luminal Received October 22, 1993; accepted June 2, 1994. From the Institut National de la Sante et de la Recherche Medicale, Paris, France. Correspondence to Dr Pierre Corvol, Co1llge de France, 3 rue d'Ulm, 75005 Paris, France. © 1994 American Heart Association, Inc. neither renal or pulmonary NEP nor pulmonary APA activities were altered. Thus, lung ACE gene expression appears to be both organand enzyme-specifically regulated during CHF. Whereas plasma renin was increased in heart failure rats, plasma Ang II levels were not different from those of control rats. Thus, decreased lung ACE activity could possibly contribute to keeping plasma Ang II levels in the normal range. The decrease in lung ACE activity and mRNA levels, combined with increased plasma ACE activity, represents a novel aspect of endothelial dysfunction in CHF. This dissociation between the membrane-bound endothelial enzyme and its circulating counterpart emphasizes the importance of simultaneously assessing the circulating and tissue components of the renin-angiotensin system in heart failure. (Circ Res. 1994;75: 454-461.)