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(Circulation Research. 2004;95:515.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Thrombospondin-2 Is Essential for Myocardial Matrix Integrity

Increased Expression Identifies Failure-Prone Cardiac Hypertrophy

Blanche Schroen^*, Stephane Heymans^*, Umesh Sharma^*, W. Matthijs Blankesteijn, Saraswati Pokharel, Jack P.M. Cleutjens, J. Gordon Porter, Chris T.A. Evelo, Rudy Duisters, Rick E.W. van Leeuwen, Ben J.A. Janssen, Jacques J.M. Debets, Jos F.M. Smits, Mat J.A.P. Daemen, Harry J.G.M. Crijns, Paul Bornstein, Yigal M. Pinto

From Experimental and Molecular Cardiology/CARIM (B.S., S.H., U.S., S.P., R.D., R.E.W.v.L., H.J.G.M.C., Y.M.P.), Department of Pharmacology and Toxicology/CARIM (W.M.B., C.T.A.E., B.J.A.J., J.J.M.D., J.F.M.S.), and Department of Pathology/CARIM (J.P.M.C., M.J.A.P.D.), University of Maastricht, Maastricht, the Netherlands; Incyte Corp. (J.G.P., C.T.A.E.), Palo Alto, Calif; Departments of Biochemistry and Medicine (P.B.), University of Washington, Seattle. The present address for J.G.P. and C.T.A.E. is CV-Therapeutics, Palo Alto, Calif.

Correspondence to Yigal M. Pinto, MD, Experimental and Molecular Cardiology, Department of Cardiology, University Hospital Maastricht, 6202 AZ Maastricht, the Netherlands. E-mail Y.Pinto{at}cardio.azm.nl

Cardiac hypertrophy can lead to heart failure (HF), but it is unpredictable which hypertrophied myocardium will progress to HF. We surmised that apart from hypertrophy-related genes, failure-related genes are expressed before the onset of failure, permitting molecular prediction of HF. Hearts from hypertensive homozygous renin-overexpressing (Ren-2) rats that had progressed to early HF were compared by microarray analysis to Ren-2 rats that had remained compensated. To identify which HF-related genes preceded failure, cardiac biopsy specimens were taken during compensated hypertrophy and we then monitored whether the rat progressed to HF or remained compensated. Among 48 genes overexpressed in failing hearts, we focused on thrombospondin-2 (TSP2). TSP2 was selectively overexpressed only in biopsy specimens from rats that later progressed to HF. Moreover, expression of TSP2 was increased in human hypertrophied hearts with decreased (0.19±0.01) versus normal ejection fraction (0.11±0.03 [arbitrary units]; P<0.05). Angiotensin II induced fatal cardiac rupture in 70% of TSP2 knockout mice, with cardiac failure in the surviving mice; this was not seen in wild-type mice. In TSP2 knockout mice, angiotensin II increased matrix metalloproteinase (MMP)-2 and MMP-9 activity by 120% and 390% compared with wild-type mice (P<0.05). In conclusion, we identify TSP2 as a crucial regulator of the integrity of the cardiac matrix that is necessary for the myocardium to cope with increased loading and that may function by its regulation of MMP activity. This suggests that expression of TSP2 marks an early-stage molecular program that is activated uniquely in hypertrophied hearts that are prone to fail.

Key Words: extracellular matrix • hypertrophy • microarray • myocardium

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