Cardiomyocyte hypercontracture Gao Qin
Background The first minutes of reperfusion repre-sent a window of opportunity for cardioprotection Development of cardiomyocyte hyper- contracture is a predominant feature of reperfusion injury
Background A pattern of contracture and necrotic cell injury “ Contraction band necrosis ” can be found during the early stage of the infarct “ Contraction band necrosis ” reflects hypercontracture of myocytes
Infarct size Contraction band necrosis
Confocal image of adult ventricular myocyte loaded with TMRM
Mechanisms of contracture Ischemia-induced contracture Rigor-type mechanism Reperfusion-induced hypercontracture Ca 2+ overload-induced contracture Rigor-type contracture
Ischemia-induced contracture Rigor-type mechanism Low cytosolic ATP myofibrillar shortening cytoskeletal defects cardiomyocytes more fragile and susceptible to mechanical damage
Reperfusion-induced hypercontracture Much greater myofibrillar shortening and cytoskeletal damage Aggravated form of contracture lead to a marked rise in end-diastolic pressure
Two causes for reperfusion- induced hypercontracture Ca 2+ overload-induced contracture energy recovery rapid but cytosolic Ca 2+ load high Rigor-type contracture energy recovery very slow
Two causes for reperfusion- induced hypercontracture
Ca 2+ overload-induced hypercontracture NHE NBS NCE reverse NCE forward NHE:Na + /H + exchanger NCE:Na + /Ca 2+ exchanger NBS: Na + /HCO 3 - symporter
Ca 2+ overload-induced hypercontracture Cyclic uptake and release of Ca 2+ by the sarcoplasmic reticulum (SR) in reoxygenated cardiomyocyte (reperfused heart) triggers a Ca 2+ oscillations-induced hypercontracture Reperfusion
Ca 2+ overload-induced hypercontracture
Treatments Initial,time-limited inhibition of the contractile machinery Phosphatase 2,3-butanedione monoxime cGMP-mediated effectors (NO,ANP) Cytosolic acidosis (-)NHE,(-)NBS reduce the Ca 2+ sensitivity of myofibrils
Treatments Reducing SR-dependent Ca 2+ oscillations Interfering with SR Ca 2+ ATPase or SR Ca 2+ release Interfering with SR Ca 2+ sequestration Inhibiting Ca 2+ influx
Rigor hypercontracture Prolonged ischemia mitochondria can not recover cardiomyocytes may contain very low concentrations of ATP at the early of re- oxygenation induce rigor-type contracture major contributor to reoxygenation-induced hypercontracture
Treatments Improving the conditions for energy recovery application of mitochondrial energy substrates (succinate) Accelerating oxidative energy production protecting mitochondria from compulsory Ca 2+ uptake Resuming oxidative phosphorylation
Spread of hypercontrature gap junctions preads cell injury
Protective signaling pathways PKC- dependent signaling PKG- dependent signaling PI 3-kinase signaling
PKC- dependent signaling Not improve the cellular state of energy or the progressive loss of control of cation homeostasis But attenuate the development of hypercontracture
PKG-dependent signaling
PI 3-kinase signaling Insulin protects the cells against hypercontracture through a PI 3- kinase-mediated pathway
References H.M. Piper, Y. Abdallah, C. Sch ä fer. The first minutes of reperfusion: a window of opportunity for cardioprotection. Cardiovascular Research 61 (2004) 365 – 371 Y. Ladilov, Ö. Efe, C. Sch ä fer, H.M. Piper et al. Reoxygenation- induced rigor-type contracture. Journal of Molecular and Cellular Cardiology 35 (2003) 1481 – 1490 H. Michael Piper, K. Meuter, C.Sch ä fer. Cellular mechanisms of ischemia-reperfusion injury. The Annals of Thoracic Surgery 75 (2003) 644 – 648 H.M. Piper, D. Garcıa-Dorado, M. Ovize. A fresh look at reperfusion injury. Cardiovascular Research 38 (1998) 291 – 300