Thrombospondin-2 is essential for myocardial matrix integrity: increased expression identifies failure-prone cardiac hypertrophy.
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.
Experimental and Molecular Cardiology/CARIM, University of Maastricht, Maastricht, the Netherlands.
Blanche
B
Schroen
Stephane
S
Heymans
Umesh
U
Sharma
W Matthijs
WM
Blankesteijn
Saraswati
S
Pokharel
Jack P M
JP
Cleutjens
J Gordon
JG
Porter
Chris T A
CT
Evelo
Rudy
R
Duisters
Rick E W
RE
van Leeuwen
Ben J A
BJ
Janssen
Jacques J M
JJ
Debets
Jos F M
JF
Smits
Mat J A P
MJ
Daemen
Harry J G M
HJ
Crijns
Paul
P
Bornstein
Yigal M
YM
Pinto
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D002303:Cardiac Output, Low / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced; D017364:Collagenases / Q000378:metabolism; D018450:Disease Progression; D004792:Enzyme Precursors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006341:Heart Rupture / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000150:complications; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D013318:Stroke Volume; D019699:Thrombospondins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation; D000099262:Thrombospondin 2
D000804:Angiotensin II; D017364:Collagenases; D004792:Enzyme Precursors; D018093:Gelatinases; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases; D012083:Renin; D019699:Thrombospondins; D000099262:Thrombospondin 2; C120487:pro-matrix metalloproteinase 9; C069860:progelatinase