Single Histidine-substituted Cardiac Troponin I Confers Protection from Age-related Systolic and Diastolic Dysfunction

Overview

Journal Cardiovasc Res

Specialty Cardiology & Vascular Diseases

Date 2008 Jul 19

PMID 18635554

Citations 14

Authors

Nathan J Palpant

Sharlene M Day

Todd J Herron

Kimber L Converso

Joseph M Metzger

Affiliations

Soon will be listed here.

Abstract

Aims: Contractile dysfunction associated with myocardial ischaemia is a significant cause of morbidity and mortality in the elderly. Strategies to protect the aged heart from ischaemia-mediated pump failure are needed. We hypothesized that troponin I-mediated augmentation of myofilament calcium sensitivity would protect cardiac function in aged mice.

Methods And Results: To address this, we investigated transgenic (Tg) mice expressing a histidine-substituted form of adult cardiac troponin I (cTnI A164H), which increases myofilament calcium sensitivity in a pH-dependent manner. Serial echocardiography revealed that Tg hearts showed significantly improved systolic function at 4 months, which was sustained for 2 years based on ejection fraction and velocity of circumferential fibre shortening. Age-related diastolic dysfunction was also attenuated in Tg mice as assessed by Doppler measurements of the mitral valve inflow and lateral annulus Doppler tissue imaging. During acute hypoxia, cardiac contractility significantly improved in aged Tg mice made evident by increased stroke volume, end systolic pressure, and +dP/dt compared with non-transgenic mice.

Conclusion: This study shows that increasing myofilament function by means of a pH-responsive histidine button engineered into cTnI results in enhanced baseline heart function in Tg mice over their lifetime, and during acute hypoxia improves survival in aged mice by maintaining cardiac contractility.

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References

Parsons B, Szczesna D, Zhao J, Van Slooten G, Kerrick W, Putkey J . The effect of pH on the Ca2+ affinity of the Ca2+ regulatory sites of skeletal and cardiac troponin C in skinned muscle fibres. J Muscle Res Cell Motil. 1997; 18(5):599-609. DOI: 10.1023/a:1018623604365. View

Davis J, Wen H, Edwards T, Metzger J . Thin filament disinhibition by restrictive cardiomyopathy mutant R193H troponin I induces Ca2+-independent mechanical tone and acute myocyte remodeling. Circ Res. 2007; 100(10):1494-502. DOI: 10.1161/01.RES.0000268412.34364.50. View

Day S, Westfall M, Fomicheva E, Hoyer K, Yasuda S, La Cross N . Histidine button engineered into cardiac troponin I protects the ischemic and failing heart. Nat Med. 2006; 12(2):181-9. DOI: 10.1038/nm1346. View

Kranias E, Bers D . Calcium and cardiomyopathies. Subcell Biochem. 2008; 45:523-37. DOI: 10.1007/978-1-4020-6191-2_20. View

Lakatta E, Levy D . Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation. 2003; 107(2):346-54. DOI: 10.1161/01.cir.0000048893.62841.f7. View

Lee J, Allen D . Mechanisms of acute ischemic contractile failure of the heart. Role of intracellular calcium. J Clin Invest. 1991; 88(2):361-7. PMC: 295338. DOI: 10.1172/JCI115311. View

Frolkis V, Frolkis R, Mkhitarian L, Shevchuk V, Fraifeld V, Vakulenko L . Contractile function and Ca2+ transport system of myocardium in ageing. Gerontology. 1988; 34(1-2):64-74. DOI: 10.1159/000212932. View

Farah C, Reinach F . The troponin complex and regulation of muscle contraction. FASEB J. 1995; 9(9):755-67. DOI: 10.1096/fasebj.9.9.7601340. View

HUNTER W . Role of myofilaments and calcium handling in left ventricular relaxation. Cardiol Clin. 2000; 18(3):443-57. DOI: 10.1016/s0733-8651(05)70155-7. View

10.

Ball K, Johnson M, Solaro R . Isoform specific interactions of troponin I and troponin C determine pH sensitivity of myofibrillar Ca2+ activation. Biochemistry. 1994; 33(28):8464-71. DOI: 10.1021/bi00194a010. View

11.

Tardiff J, Hewett T, Palmer B, Olsson C, Factor S, Moore R . Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy. J Clin Invest. 1999; 104(4):469-81. PMC: 408522. DOI: 10.1172/JCI6067. View

12.

Metzger J, Westfall M . Covalent and noncovalent modification of thin filament action: the essential role of troponin in cardiac muscle regulation. Circ Res. 2004; 94(2):146-58. DOI: 10.1161/01.RES.0000110083.17024.60. View

13.

Westfall M, Metzger J . Single amino acid substitutions define isoform-specific effects of troponin I on myofilament Ca2+ and pH sensitivity. J Mol Cell Cardiol. 2007; 43(2):107-18. PMC: 2043486. DOI: 10.1016/j.yjmcc.2007.05.017. View

14.

Dargis R, Pearlstone J, Barrette-Ng I, Edwards H, Smillie L . Single mutation (A162H) in human cardiac troponin I corrects acid pH sensitivity of Ca2+-regulated actomyosin S1 ATPase. J Biol Chem. 2002; 277(38):34662-5. DOI: 10.1074/jbc.C200419200. View

15.

Takeda S, Yamashita A, Maeda K, Maeda Y . Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form. Nature. 2003; 424(6944):35-41. DOI: 10.1038/nature01780. View

16.

Hasenfuss G, Pieske B . Calcium cycling in congestive heart failure. J Mol Cell Cardiol. 2002; 34(8):951-69. DOI: 10.1006/jmcc.2002.2037. View

17.

Koretsune Y, Marban E . Cell calcium in the pathophysiology of ventricular fibrillation and in the pathogenesis of postarrhythmic contractile dysfunction. Circulation. 1989; 80(2):369-79. DOI: 10.1161/01.cir.80.2.369. View

18.

Jahangir A, Sagar S, Terzic A . Aging and cardioprotection. J Appl Physiol (1985). 2007; 103(6):2120-8. DOI: 10.1152/japplphysiol.00647.2007. View

19.

Michaud C, Murray C, Bloom B . Burden of disease--implications for future research. JAMA. 2001; 285(5):535-9. DOI: 10.1001/jama.285.5.535. View

20.

Deedwania P . The key to unraveling the mystery of mortality in heart failure: an integrated approach. Circulation. 2003; 107(13):1719-21. DOI: 10.1161/01.CIR.0000014688.12415.C0. View