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