| First Author | Zhu Y | Year | 2008 |
| Journal | Proc Natl Acad Sci U S A | Volume | 105 |
| Issue | 14 | Pages | 5519-24 |
| PubMed ID | 18378906 | Mgi Jnum | J:133770 |
| Mgi Id | MGI:3784125 | Doi | 10.1073/pnas.0801779105 |
| Citation | Zhu Y, et al. (2008) Tbx5-dependent pathway regulating diastolic function in congenital heart disease. Proc Natl Acad Sci U S A 105(14):5519-24 |
| abstractText | At the end of every heartbeat, cardiac myocytes must relax to allow filling of the heart. Impaired relaxation is a significant factor in heart failure, but all pathways regulating the cardiac relaxation apparatus are not known. Haploinsufficiency of the T-box transcription factor Tbx5 in mouse and man causes congenital heart defects (CHDs) as part of Holt-Oram syndrome (HOS). Here, we show that haploinsufficiency of Tbx5 in mouse results in cell-autonomous defects in ventricular relaxation. Tbx5 dosage modulates expression of the sarco(endo)plasmic reticulum Ca(2+)-ATPase isoform 2a encoded by Atp2a2 and Tbx5 haploinsufficiency in ventricular myocytes results in impaired Ca(2+) uptake dynamics and Ca(2+) transient prolongation. We also demonstrate that Tbx5 can activate the Atp2a2 promoter. Furthermore, we find that patients with HOS have significant diastolic filling abnormalities. These results reveal a direct genetic pathway that regulates cardiac diastolic function, implying that patients with structural CHDs may have clinically important underlying anomalies in heart function that merit treatment. |
