Heart hypertrophy in response to pressure overload in TSP4 knockout mice

Thrombospondin‐4 (TSP4) is abundant in the heart in blood vessels, including capillaries and the aorta. TSP4 expression increases in hypertrophic and failing hearts and in response to ischemia. TSP4 KO and WT mice were subjected to transverse aortic constriction (TAC). 2 and 20 weeks later TSP4 KO hearts revealed more extensive hypertrophy and higher HW/BW (heart weight/ body weight) ratio compared to WT mice, and the differences were magnified with age: 6.7(0.2 in WT versus 7.4(0.2 in KO of 23 weeks, 4.7(1 in WT versus 9(3 KO at 55 weeks, and 4.3(0.8 in WT versus 8.5(3 in KO at 82 weeks. The increased hypertrophy in TAC TSP4 KO mice was due to higher deposition of collagen. The fibrosis fraction was calculated as the ratio of Masson's trichrome stained connective tissue area to total myocardial area: WT ‐ 7.4%(2.6, KO ‐ 9.6%(5.9 at 23 weeks 20 weeks after TAC; WT ‐ 3.8%(2, KO ‐ 11.2%(8.4 at 55 weeks, 20 weeks after TAC; and WT ‐ 4.6%(2.1, KO ‐ 16.8%(3 at 82 weeks, 2 weeks after TAC. TSP4 KO hearts experienced the overload even in normal conditions: the cardiomyocytes in sham operated KO trended to be smaller in size; in hearts of old sham KO mice fibrosis fraction was 2 times larger than in WT mice hearts and non‐operated KO hearts showed 1.8 fold increase in glucose uptake. We conclude that TSP4 is involved in adaptive responses of the heart to pressure overload, suggesting its important role in tissue remodeling. P50 HL077107 ; R01 DK067532