Transgenic mouse model of stunned myocardium.

Stunned myocardium is a syndrome of reversible contractile failure that frequently complicates coronary artery disease. Cardiac excitation is uncoupled from contraction at the level of the myofilaments. Selective proteolysis of the thin filament protein troponin I has been correlated with stunned myocardium. Here, transgenic mice expressing the major degradation product of troponin I (TnI1-193) in the heart were found to develop ventricular dilatation, diminished contractility, and reduced myofilament calcium responsiveness, recapitulating the phenotype of stunned myocardium. Proteolysis of troponin I also occurs in ischemic human cardiac muscle. Thus, troponin I proteolysis underlies the pathogenesis of a common acquired form of heart failure.

[1]  J. Canty,et al.  Absence of troponin I degradation or altered sarcoplasmic reticulum uptake protein expression after reversible ischemia in swine. , 1999, Circulation research.

[2]  J. V. Van Eyk,et al.  In search of the proteins that cause myocardial stunning. , 1999, Circulation research.

[3]  J. Lorenz,et al.  Abnormal Cardiac Structure and Function in Mice Expressing Nonphosphorylatable Cardiac Regulatory Myosin Light Chain 2* , 1999, The Journal of Biological Chemistry.

[4]  C. Ramos.  Mapping Subdomains in the C-terminal Region of Troponin I Involved in Its Binding to Troponin C and to Thin Filament* , 1999, The Journal of Biological Chemistry.

[5]  A. Børglum,et al.  α-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy , 1999 .

[6]  R. Moss,et al.  Impaired cardiomyocyte relaxation and diastolic function in transgenic mice expressing slow skeletal troponin I in the heart , 1999, The Journal of physiology.

[7]  E. Marbán,et al.  Molecular and cellular mechanisms of myocardial stunning. , 1999, Physiological reviews.

[8]  J. Seidman,et al.  Altered cardiac excitation-contraction coupling in mutant mice with familial hypertrophic cardiomyopathy. , 1999, The Journal of clinical investigation.

[9]  Dimitrios Georgakopoulos,et al.  The pathogenesis of familial hypertrophic cardiomyopathy: Early and evolving effects from an α-cardiac myosin heavy chain missense mutation , 1999, Nature Medicine.

[10]  D. K. Arrell,et al.  Troponin I degradation and covalent complex formation accompanies myocardial ischemia/reperfusion injury. , 1999, Circulation research.

[11]  T. Hewett,et al.  A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy. , 1998, The Journal of clinical investigation.

[12]  R. Hodges,et al.  Breakdown and release of myofilament proteins during ischemia and ischemia/reperfusion in rat hearts: identification of degradation products and effects on the pCa-force relation. , 1998, Circulation research.

[13]  J. Towbin,et al.  The role of cytoskeletal proteins in cardiomyopathies. , 1998, Current opinion in cell biology.

[14]  E. Marbán,et al.  Calcium cycling and contractile activation in intact mouse cardiac muscle , 1998, The Journal of physiology.

[15]  K. McDonald,et al.  Incorporation of the troponin regulatory complex of post-ischemic stunned porcine myocardium reduces myofilament calcium sensitivity in rabbit psoas skeletal muscle fibers. , 1998, Journal of molecular and cellular cardiology.

[16]  R. Solaro,et al.  The C Terminus of Cardiac Troponin I Is Essential for Full Inhibitory Activity and Ca2+ Sensitivity of Rat Myofibrils* , 1997, The Journal of Biological Chemistry.

[17]  M. Matsuzaki,et al.  Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy , 1997, Nature Genetics.

[18]  D. Atar,et al.  Role of troponin I proteolysis in the pathogenesis of stunned myocardium. , 1997, Circulation research.

[19]  T. Hewett,et al.  Ablation of the murine alpha myosin heavy chain gene leads to dosage effects and functional deficits in the heart. , 1996, The Journal of clinical investigation.

[20]  Frederick J. Schoen,et al.  A Mouse Model of Familial Hypertrophic Cardiomyopathy , 1996, Science.

[21]  Yongge Liu,et al.  Intrinsic myofilament alterations underlying the decreased contractility of stunned myocardium. A consequence of Ca2+-dependent proteolysis? , 1996, Circulation research.

[22]  D. Atar,et al.  Relationship between intracellular calcium and contractile force in stunned myocardium. Direct evidence for decreased myofilament Ca2+ responsiveness and altered diastolic function in intact ventricular muscle. , 1995, Circulation research.

[23]  E. Marbán,et al.  Cellular mechanisms of myocardial stunning. , 1992, Annual review of physiology.

[24]  J. Robbins,et al.  Tissue-specific regulation of the alpha-myosin heavy chain gene promoter in transgenic mice. , 1991, The Journal of biological chemistry.

[25]  A. Murphy,et al.  Troponin I isoform expression in human heart. , 1991, Circulation research.

[26]  C. Hartley,et al.  Beta-adrenergic stimulation reverses postischemic myocardial dysfunction without producing subsequent functional deterioration. , 1985, The American journal of cardiology.

[27]  B Buis,et al.  Continuous measurement of left ventricular volume in animals and humans by conductance catheter. , 1984, Circulation.