Abstract 360: Differential Analysis of Thrombospondin Proteins in Cardiac Disease

Abstract

Thrombospondin (Thbs) proteins are multidomain, matricellular proteins comprised of 5 genes that each share similar domains and have been largely ascribed the same functional characteristics The Thbs protein family is divided in 2 subgroups based on multimerization as trimers, (group A: Thbs1 and 2), or as pentamers (group B: Thbs3, 4 and 5). Thbs proteins modulate aspects of cell- matrix interactions, and more recently we have shown that they can also serve an intracellular chaperone function along the secretory pathway in response to ER stress. Thbs1 and 2 can also alter angiogenesis and modulate MMP activity as well as TGFb activity. The overall aim of this study is to functionally compare the two Thbs subgroups and elucidate their involvement in cardiac homeostasis and disease. Hence we analyzed Thbs1 as a representative of group A and Thbs3 for group B. Cardiomyocyte specific overexpression of either Thbs1 or Thbs3 results in robust activation of an ATF6- dependent ER stress response, similar to our previous working published with Thbs4. However, Thbs1 overexpressing mice suffer from cardiomyopathy and die within 12 weeks. In contrast, Thbs3 overexpressing mice are completely normal at baseline and Thbs3 overexpression even increased survival rates after MI similar to Thbs4 from our previous work. However, Thbs3 hearts also showed increased chamber dilation after MI and lower heart function suggesting that Thbs3 also has maladaptive effects. In contrast to loss of Thbs4, which die within the first week of TAC mediated pressure overload, Thbs3 KO mice are protected from TAC induced hypertrophy. Moreover, the combination of Thbs3/4 dKO more closely phenocopies the effect of Thbs3 deletion, as these mice show a significant reduction in hypertrophy and lung congestion after long term TAC. This is the first study comparing the function of different Thbs isoforms in the heart, which suggests a novel role of Thbs3.