Titin isoform switch in ischemic human heart disease.
BACKGROUND
Ischemia-induced cardiomyopathy usually is accompanied by elevated left ventricular end-diastolic pressure, which follows from increased myocardial stiffness resulting from upregulated collagen expression. In addition to collagen, a main determinant of stiffness is titin, whose role in ischemia-induced left ventricular stiffening was studied here. Human heart sarcomeres coexpress 2 principal titin isoforms, a more compliant N2BA isoform and a stiffer N2B isoform. In comparison, normal rat hearts express almost no N2BA titin.


RESULTS
Gel electrophoresis and immunoblotting were used to determine the N2BA-to-N2B titin isoform ratio in nonischemic human hearts and nonnecrotic left ventricle of coronary artery disease (CAD) patients. The average N2BA-to-N2B ratio was 47:53 in severely diseased CAD transplanted hearts and 32:68 in nonischemic transplants. In normal donor hearts and donor hearts with CAD background, relative N2BA titin content was approximately 30%. The titin isoform shift in CAD transplant hearts coincided with a high degree of modifications of cardiac troponin I, probably indicating increased preload. Immunofluorescence microscopy on CAD transplant specimens showed a regular cross-striated arrangement of titin and increased expression of collagen and desmin. Force measurements on isolated myofibrils revealed reduced passive-tension levels in sarcomeres of CAD hearts with high left ventricular end-diastolic pressure compared with sarcomeres of normal hearts. In a rat model of ischemia-induced myocardial infarction (left anterior descending coronary artery ligature), 43% of animals, but only 14% of sham-operated animals, showed a distinct N2BA titin band on gels.


CONCLUSIONS
A titin isoform switch was observed in chronically ischemic human hearts showing extensive remodeling, which necessitated cardiac transplantation. The shift, also confirmed in rat hearts, caused reduced titin-derived myofibrillar stiffness. Titin modifications in long-term ischemic myocardium could impair the ability of the heart to use the Frank-Starling mechanism.
Neagoe
Ciprian
C
Institute of Physiology and Pathophysiology, University of Heidelberg, Germany.
Kulke
Michael
M
del Monte
Federica
F
Gwathmey
Judith K
JK
de Tombe
Pieter P
PP
Hajjar
Roger J
RJ
Linke
Wolfgang A
WA
D000818:Animals; D003094:Collagen / Q000378:metabolism; D003187:Compliance; D064211:Connectin; D003327:Coronary Disease / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D003331:Coronary Vessels / Q000601:surgery; D003893:Desmin / Q000378:metabolism; D005260:Female; D006333:Heart Failure / Q000378:metabolism; D016027:Heart Transplantation; D006801:Humans; D008026:Ligation; D009124:Muscle Proteins / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D009206:Myocardium / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019210:Troponin I / Q000378:metabolism
D064211:Connectin; D003893:Desmin; D009124:Muscle Proteins; D020033:Protein Isoforms; C577285:TTN protein, human; D019210:Troponin I; D003094:Collagen; D011494:Protein Kinases