The Role of Cardiac Troponin T Quantity and Function in Cardiac Development and Dilated Cardiomyopathy

被引：52

作者：

Ahmad, Ferhaan ^{[1
,2
,3
]}

Banerjee, Sanjay K. ^{[1
]}

Lage, Michele L. ^{[1
]}

Huang, Xueyin N. ^{[1
]}

Smith, Stephen H. ^{[4
]}

Saba, Samir ^{[1
]}

Rager, Jennifer ^{[1
]}

Conner, David A. ^{[3
]}

Janczewski, Andrzej M. ^{[4
]}

Tobita, Kimimasa ^{[5
]}

Tinney, Joseph P. ^{[5
]}

Moskowitz, Ivan P. ^{[6
]}

Perez-Atayde, Antonio R. ^{[6
]}

Keller, Bradley B. ^{[5
]}

Mathier, Michael A. ^{[1
]}

Shroff, Sanjeev G. ^{[4
]}

Seidman, Christine E. ^{[3
]}

Seidman, J. G. ^{[3
]}

机构：

[1] Univ Pittsburgh, Dept Med, Cardiovasc Inst, Pittsburgh, PA 15260 USA

[2] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA

[3] Harvard Med Sch, Howard Hughes Med Inst, Dept Genet, Boston, MA USA

[4] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA

[5] Univ Pittsburgh, Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA USA

[6] Childrens Hosp, Dept Pathol, Boston, MA USA

来源：

PLOS ONE | 2008年 / 3卷 / 07期

关键词：

D O I：

10.1371/journal.pone.0002642

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies result from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca(2+) desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis. Methods and Findings: We ablated Tnnt2 to produce heterozygous Tnnt2(+/-) mice, and crossbreeding produced homozygous null Tnnt2(-/-) embryos. We also generated transgenic mice overexpressing wildtype (TG(WT)) or DCM mutant (TG(K210 Delta)) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype ( Tnnt2(+/-)/TG(WT)) or mutant (Tnnt2(+/-)/ TG(K210 Delta)) transgenes. Tnnt2(+/-) mice relative to wildtype had significantly reduced transcript (0.82 +/- 0.06[SD] vs. 1.00 +/- 0.12 arbitrary units; p = 0.025), but not protein (1.01 +/- 0.20 vs. 1.00 +/- 0.13 arbitrary units; p = 0.44). Tnnt2(+/-) mice had normal hearts ( histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2(+/-)/TGK(210 Delta) mice had severe DCM, TGK(210 Delta) mice had only mild DCM (FS 18 +/- 4 vs. 29 +/- 7%; p<0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2(+/-)/TGK(210 Delta) relative to TGK(210 Delta) mice (2.42 +/- 0.08, p = 0.03). Tnnt2(+/-)/TGK(210 Delta) muscle showed Ca(2+) desensitization (pCa(50) = 5.34 +/- 0.08 vs. 5.58 +/- 0.03 at sarcomere length 1.9 mu m, p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2(-/-) embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres. Conclusions: Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca(2+) desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity.

引用

页数：11

共 33 条

[1] Cardiac length dependence of force and force redevelopment kinetics with altered cross-bridge cycling [J].