Abstract 63: Absence of Fibulin-2 Attenuates Cardiac Hypertrophy and Fibrosis in Transgenic Mice Over-expressing Circulating Transforming Growth Factor-beta
Background: TGF-β is a potent growth factor that induces myocardial hypertrophy and fibrosis. However, the interaction between circulating TGF-β and local myocardial TGF-β in inducing cardiac hypertrophy is not well understood. Fibulin-2 is an ECM protein that mediates TGF-β activation during cardiac hypertrophy in response to chronic angiotensin (Ang) II infusion. We tested the hypothesis that fibulin-2 mediates systemic TGF-β-induced cardiac hypertrophy.
Materials & Methods and Results: We created double mutant mice by crossing TGF-β over-expressing transgenic mice (TG) and fibulin-2 knockout mice (KO). TG are known to produce excessive mature porcine TGF-β from the liver. TG/WT developed significant myocardial hypertrophy at 8 weeks compared with non-TG (NTG) groups. Hypertrophy in KO/TG was significantly attenuated compared with TG/WT. Myocardial TGF-β mRNA up-regulation was significantly higher in TG/WT than in TG/KO or NGT groups, so was Smad2 activation, but myocardial TGF-β bioactivity measured by PAI-1 promoter/luciferase bioassay was comparable among all four groups. Serum carrier-bound TGF-β (total TGF-β) in WT/TG was significantly higher than that in KO/TG and NTG groups, but free TGF-β level was equally elevated in TG groups compared with NTG groups. The difference in hypertrophy between WT/TG and KO/TG may be attributed to increased myocardial TGF-β[[Unable to Display Character: ]]mRNA and elevated serum total TGF-β in WT/TG, not directly to bioactive myocardial TGF-β[[Unable to Display Character: ]]or serum free TGF-β. Endogenous TGF-β mRNA levels in kidney and liver were equally increased in TG groups compared with NTG groups, and were same in all 4 groups in lung, suggesting fibulin-2 was not involved in TGF-β-induced TGF-β synthesis in these organs.
Conclusion: Systemic TGF-β-induced-endogenous TGF-β up-regulation was mediated by fibulin-2 in the myocardium. After secretion, endogenous myocardial TGF-β may be either sequestrated into insoluble ECM or directly released into circulation as a soluble carrier-bound form. It is circulating endogenous TGF-β secreted from the heart that is primarily responsible for myocardial hypertrophy. Heart is a major source of circulating endogenous TGF-β in the TG/WT, which assumes an endocrine role in inducing myocardial hypertrophy.
Author Disclosures: T. Tsuda: None. S. Khan: None.
- © 2015 by American Heart Association, Inc.