Abstract 3732: Thrombospondin-4 is Necessary for Hearts to Adapt to Pressure Overload
Thrombospondin-4 (TSP4) is a matricellular protein found predominantly in skeletal and heart muscle. Its expression is upregulated in animal models of heart failure and in humans with ischemic or non-ischemic cardiomyopathy; however, the role it plays in cardiac regulation is unknown. We therefore studied mice that globally lacked the TSP4 gene (tsp4−/−). At rest, hearts from tsp4−/− appear normal, and have normal function. However, upon exposure to acute pressure overload (transverse aortic constriction, TAC), tsp4−/− hearts acutely dilate and indexes of contractility decline within minutes (pressure-volume relation analysis). This contrasts to littermate (ntg) controls that increase contractility and compensate for the loading (i.e. Anrep effect, Figure⇓). In ntg dP/dt max rose 19±4% after 30 min, but fell 25±6% in tsp4−/−, p<0.001. These results were reproduced in isolated ventricular trabeculae, where force rose rapidly with a stretch followed by a slow further rise in controls, but a marked decline in tsp4−/−. Basal myocyte function (sarcomere shortening and calcium transients) was similar between tsp4−/− and ntg, but shortening declined after 48hrs-TAC in tsp4−/− hearts (p<0.01). At this time point, tsp4−/− hearts had myocyte disarray and by 3 weeks dilated hypertrophy with extensive interstitial fibrosis (WT: 3.43±0.81%, TSP4−/−: 12.13±1.15 %, p<0.001). TGF-β and CTGF mRNA levels rose in tsp4−/− at 48 hrs and 3 wks-TAC. These data show TSP4 is necessary for acute cardiac adaptation to pressure overload. Its absence disrupts stress-myocyte coupling and triggers sustained signaling that worsens eccentric hypertrophy and fibrosis.