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(Circulation. 2004;110:1767-1773.)
© 2004 American Heart Association, Inc.

Coronary Heart Disease

Different Quantitative Apoptotic Traits in Coronary Atherosclerotic Plaques From Patients With Stable Angina Pectoris and Acute Coronary Syndromes

Marco L. Rossi, MD; Nicola Marziliano, PhD; Piera Angelica Merlini, MD; Ezio Bramucci, MD; Umberto Canosi, MD; Guido Belli, MD; Dennis Zavalloni Parenti, MD; Pier Mannuccio Mannucci, MD; Diego Ardissino, MD

From the Division of Cardiology, Istituto Clinico Humanitas, Milan (M.L.R., G.B., D.Z.P.); Developmental Biology Laboratory, University of Pavia, Pavia (N.M.); IV Division of Cardiology, Ospedale Niguarda, Milan (P.A.M.); Division of Cardiology, IRCCS, Policlinico S Matteo, Pavia (E.B., U.C.); Hemophilia and Thrombosis Center and Institute of Internal Medicine, IRCCS, Ospedale Maggiore, University of Milan, Milan (P.M.M.); and Division of Cardiology, Ospedale Maggiore, Parma (D.A.), Italy.

Correspondence to Marco L. Rossi, Divisione di Cardiologia, Unità Operativa di Emodinamica, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano MI, Italy. E-mail marcolrossi{at}hotmail.com

Received November 5, 2003; de novo received March 22, 2004; revision received May 12, 2004; accepted May 19, 2004.

Background— Apoptosis in human atherosclerotic coronary plaques possibly causes plaque destabilization by contributing to the weakening and breaking down of the fibrous cap. We tested the hypothesis that apoptosis is quantitatively increased in unstable atherosclerotic plaques.

Methods and Results— We analyzed the expression of apoptotic genes such as BAX, CASP1, FAS, FAS L, FOS, MDM2, NFkB2, P53, PCNA, TERT, and XRCC1 in coronary plaques collected with directional coronary atherectomy from 15 patients with stable angina and 15 with acute coronary syndromes without ST elevation (ACS). Total RNA was extracted and cDNA was amplified with a specific set of primers and TaqMan probes. Apoptosis was also revealed by DNA laddering. To clarify the source of mRNAs, we performed in situ reverse transcriptase-polymerase chain reaction coupled with immunocytochemistry and found a substantial overlap between the mRNAs of the above genes and vascular smooth muscle cells. Gene expression analysis showed that the proapoptotic genes (ie, BAX, CASP1, FAS, FAS L, FOS, NFkB2, P53, PCNA) were significantly more expressed (P<0.001) in ACS plaques, whereas the antiapoptotic genes (ie, MDM2, TERT, XRCC1) were more transcribed (P<0.001) in stable angina plaques. Total gDNA gel electrophoresis identified a laddering pattern in the ACS plaques as evidence of end-point apoptosis. Western blotting substantially confirmed the above data.

Conclusions— Our findings support the idea that ACS plaques are committed to apoptosis through an established meshwork of gene activation and inactivation, whereas stable angina plaques retain active cell homeostasis and repair mechanisms.

Key Words: acute coronary syndromes • angina • apoptosis • atherosclerosis • gene expression

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