Cardiomyocyte hypercontractur e Gao Qin
Jan 03, 2016
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 th
e 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 Ca2+ overload-induced contracture Rigor-type contracture
Ischemia-induced contracture
• Rigor-type mechanism Low cytosolic ATP myofibrillar shor
tening 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
• Ca2+ overload-induced contracture energy recovery rapid but cytosolic Ca2+ load high • Rigor-type contracture energy recovery very slow
Two causes for reperfusion- induced hypercontracture
Ca2+ overload-induced hypercontracture
NHENBS
NCE reverse
NCE forward
NHE:Na+/H+ exchanger NCE:Na+/Ca2+ exchanger NBS: Na+/HCO3- symporter
Ca2+ overload-induced hypercontracture
• Cyclic uptake and release of Ca2+ by the sarcoplasmic reticulum (SR) in reoxygenated cardiomyocyte (reperfused heart) triggers a Ca2+ oscillations-induced hypercontracture
Reperfusion
Ca2+ 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 Ca2+ sensitivity of myofibrils
Treatments
• Reducing SR-dependent Ca2+ oscillations• Interfering with SR Ca2+ ATPase or SR Ca2+
release• Interfering with SR Ca2+ sequestration• Inhibiting Ca2+ influx
Rigor hypercontracture• Prolonged ischemia mitochondria can not re
cover cardiomyocytes may contain very low concentrations of ATP at the early of re- oxygenation induce rigor-type contracture
major contributor toreoxygenation-induced
hypercontracture
Treatments
• Improving the conditions for energy recovery
•application of mitochondrial energy substrates (succinate)
Accelerating oxidative energy production
•protecting mitochondria from compulsory Ca2+ uptake
Resuming oxidative phosphorylation
Spread of hypercontrature
gap junctionspreads cell injury
Protective signaling pathways
• PKC-dependent signali
ng• PKG-depen
dent 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. Schäfer. The first minutes of reperfusion: a window of opportunity for cardioprotection. Cardiovascular Research 61 (2004) 365– 371
• Y. Ladilov, Ö. Efe, C. Schäfer, 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.Schäfer. Cellular mechanisms of ischemia-reperfusion injury. The Annals of Thoracic Surgery 75 (2003) 644–648 • H.M. Piper, D. Garc a-Dorado, M. Ovize. ı A fresh look at
reperfusion injury. Cardiovascular Research 38 (1998) 291–300