Specific enhancement of sarcomeric response to Ca2+ protects murine myocardium against ischemia-reperfusion dysfunction.
Alteration in myofilament response to Ca2+ is a major mechanism for depressed cardiac function after ischemia-reperfusion (I/R) dysfunction. We tested the hypothesis that hearts with increased myofilament response to Ca2+ are less susceptible to I/R. In one approach, we studied transgenic (TG) mice with a constitutive increase in myofilament Ca2+ sensitivity in which the adult form of cardiac troponin I (cTnI) is stoichiometrically replaced with the embryonic/neonatal isoform, slow skeletal TnI (ssTnI). We also studied mouse hearts with EMD-57033, which acts specifically to enhance myofilament response to Ca2+. We subjected isolated, perfused hearts to an I/R protocol consisting of 25 min of no-flow ischemia followed by 30 min of reperfusion. After I/R, developed pressure and rates of pressure change were significantly depressed and end-diastolic pressure was significantly elevated in nontransgenic (NTG) control hearts. These changes were significantly blunted in TG hearts and in NTG hearts perfused with EMD-57033 during reperfusion, with function returning to nearly baseline levels. Ca2+- and cross bridge-dependent activation, protein breakdown, and phosphorylation in detergent-extracted fiber bundles were also investigated. After I/R NTG fiber bundles exhibited a significant depression of cross bridge-dependent activation and Ca2+-activated tension and length dependence of activation that were not evident in TG preparations. Only NTG hearts demonstrated a significant increase in cTnI phosphorylation. Our results support the hypothesis that specific increases in myofilament Ca2+ sensitivity are able to diminish the effect of I/R on cardiac function.
Arteaga
Grace M
GM
Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, IL 60612, USA. gracea@uic.edu
Warren
Chad M
CM
Milutinovic
Sanja
S
Martin
Anne F
AF
Solaro
R John
RJ
D008841:Actin Cytoskeleton / Q000502:physiology; D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D000831:Animals, Newborn; D001696:Biomechanical Phenomena; D001794:Blood Pressure / Q000502:physiology; D002118:Calcium / Q000502:physiology*; D003326:Coronary Circulation; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D010766:Phosphorylation; D011804:Quinolines / Q000494:pharmacology; D012518:Sarcomeres / Q000502:physiology*; D013318:Stroke Volume / Q000502:physiology; D013829:Thiadiazines / Q000494:pharmacology; D019210:Troponin I / Q000737:chemistry / Q000502:physiology
D011804:Quinolines; D013829:Thiadiazines; D019210:Troponin I; C070609:EMD 53998; D002118:Calcium