In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 123, No. Suppl_1 ( 2018-08-03)
Abstract:
Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB) harbor cardioprotective qualities that may attenuate CM. In a small cohort of DMD patients we found that BDNF blood levels positively correlated with preserved ejection fraction (EF) and less fibrosis, and carriers of the common BDNF single nucleotide polymorphism rs6265 (Val66-Met) tended to exhibit earlier age of onset of fibrosis with subsequent progression to LV dysfunction, compared to non-carriers. We thus hypothesized that BDNF/TrkB signaling delays CM progression in DMD. To test this hypothesis, we administered the TrkB agonist 7,8-dihydroxyflavone (DHF) to mdx 4cv ; mTR KO mice in their drinking water for 26 weeks, beginning at 8 weeks of age. Based on echocardiography, DHF treatment preserved cardiac output compared to vehicle-treated controls. Conversely, mdx 4cv ; mTR KO mice injected intraperitoneally with the TrkB inhibitor (K252a) displayed bradycardia and PR interval prolongation, as measured by EKG, as well as acute (10-20 min) reduction in percent EF and fractional shortening, as measured by echocardiography. K252a also significantly reduced sarcomere shortening in isolated murine cardiomyocytes. BDNF might also contribute to cardiac repair. Using humanized BDNF polymorphic mice, which have the Val66-Met mutation, we found that post-myocardial infarction cardiac dysfunction was significantly exacerbated in Met/Met mice compared to Val/Val littermate controls. Finally, we evaluated the role of BDNF/TrkB in human cardiomyocytes differentiated from induced pluripotent cells obtained from DMD patients (DMD iPSC-CMs) and found that they highly express BDNF protein in lysates and supernatants. DMD iPSC-CMs also expressed a truncated version of TrkB that lacks the tyrosine kinase domain essential for canonical BDNF/TrkB signaling. Nonetheless, DMD iPSC-CMs responded to treatment with recombinant BDNF, including increased phosphorylation of GSK-3α, mTOR, AMPK, and MSK1/2. Considered together, our results indicate that BDNF plays a protective role in the dystrophic heart and might represent a novel therapeutic candidate for DMD cardiomyopathy.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/res.123.suppl_1.114
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2018
detail.hit.zdb_id:
1467838-X
Permalink
