Table 2.

Role of the Thrombospondins in cardiac homeostasis and disease

	TSP-1	TSP-2	TSP-3, TSP-4, TSP-5
Cardiac homeostasis	Very low expression in normal hearts and no major role in cardiac homeostasis. TSP-1 −/− mouse hearts exhibit preserved systolic function and normal wall thickness (278). An association between TSP-1 deficiency and modest increases in vascular density (by 10–15%) and chamber dimensions (by 8%) has been reported (278). TSP-1 has a limited role in blood pressure regulation: TSP-1 loss results in a modest increase in diastolic and mean blood pressure during activity (198).	Very low expression in normal adult hearts (436). No known role in cardiac homeostasis in young animals.	TSP-4 is highly expressed in normal hearts (250); however, its role in cardiac homeostasis is unknown.
Cardiac aging	No known role in cardiac aging.	TSP-2 plays an essential protective role in the aging myocardium (436). Aging TSP-2 −/− mice have markedly increased mortality, associated with severe dilated cardiomyopathy, impaired systolic function and fibrosis. TSP-2-induced protection in the aging myocardium is due to activation of pro-survival Akt signalling in cardiomyocytes and to inhibition of MMPs.	No known role in cardiac aging.
Myocardial infarction	TSP-1 is markedly upregulated in the infarct border zone and may serve as a “barrier” protecting the non-infarcted myocardium from extension of inflammation and matrix degradation, thus preventing adverse remodelling (148). TSP-1 null mice exhibit enhanced adverse remodelling following infarction associated with extension of the inflammatory reaction into the non-infarcted myocardium and with impaired TGF-beta activation. Protective effects of TSP-1 may also be mediated through inhibition of MMP activity.	A protective role of TSP-2 in the infarcted heart has been suggested. TSP-2 loss was associated with a higher incidence of cardiac rupture suggesting a role in maintaining the structural integrity of the remodelling matrix network.	No known role in myocardial infarction.
Cardiac hypertrophy and fibrosis	TSP-1 protects the pressure-overloaded myocardium from dilative remodelling favouring matrix preservation (490). TSP-1 null mice exhibited attenuated dilation in a model of transverse aortic constriction. The protective effects of TSP-1 appear to be due to better matrix preservation mediated through inhibitory effects on MMP activity and through TGF-β activation. In diabetic animals with pressure overload a peptide antagonist of TSP-1-mediated TGF-β activation prevented the progression of cardiac fibrosis (35).	TSP-2 protects the pressure overloaded myocardium my maintaining matrix integrity. Following angiotensin infusion TSP-2 null mice exhibit increased mortality due to cardiac rupture, reflecting defective collagen fibril assembly (401).	Expression of pentameric TSPs is upregulated in remodeling hearts, particularly during the transition to heart failure. Myocardial TSP-3 mRNA expression is upregulated in hypertensive renin-overexpressing rats showing evidence of decompensation (401). TSP-4 expression is increased in pressure-overloaded hearts (373) and in the myocardium of animals undergoing angiotensin or arginine-vasopressin infusion (311)..
Toxic cardiomyopathies	No known role.	TSP-2 protects the myocardium from doxorubicin-induced cardiomyopathy by promoting cardiomyocyte survival and by inhibiting matrix degradation (460).
TSPs in human heart disease	TSP-1 expression is increased in chronically ischemic myocardium from patients undergoing bypass surgery (158). TSP-1 in blood cells predicted functional deterioration in patients with acute myocardial infarction (113). The Ser-700 TSP-1 variant is associated with enhanced platelet aggregation and premature coronary disease (454).	TSP-2 expression is increased in hypertrophied (401) and chronically ischemic human myocardium (158). A TSP-2 variant has been associated with protection from myocardial infarction (454).	TSP-4 expression is increased in hypertrophied, failing and chronically ischemic human myocardium (445), (158). A TSP-4 missense variant (A387P) is strongly associated with myocardial infarction (454).