CRYAB and HSPB2 deficiency increases myocyte mitochondrial permeability transition and mitochondrial calcium uptake

Kadono, Toshie; Zhang, Xiu Quan; Srinivasan, Sathya; Ishida, Hideyuki; Barry, William H.; Benjamin, Ivor J.

doi:10.1016/j.yjmcc.2006.03.003

Cited by 41 publications

(44 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Finally, a form of ␣BC that mimics P-␣BC-S59, ␣BC-AAE, effectively inhibited MPT pore opening on mitochondria, in vitro, consistent with a functional role for this form of ␣BC at the mitochondrial level. The latter findings are consistent with two recent studies showing an increase in calcium-induced MPT pore opening in mitochondria prepared from mice that lack ␣BC compared with wild-type mouse mitochondria (18,36).…”

Section: Discussionsupporting

confidence: 93%

Localization of phosphorylated αB-crystallin to heart mitochondria during ischemia-reperfusion

Jin

Whittaker²,

Glassy³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Jin JK, Whittaker R, Glassy MS, Barlow SB, Gottlieb RA, Glembotski CC. Localization of phosphorylated ␣B-crystallin to heart mitochondria during ischemia-reperfusion. Am J Physiol Heart Circ Physiol 294: H337-H344, 2008. First published November 9, 2007 doi:10.1152/ajpheart.00881.2007.-The cytosolic small heat shock protein ␣B-crystallin (␣BC) is a molecular chaperone expressed in large quantities in the heart, where it protects from stresses such as ischemia-reperfusion (I/R). Upon I/R, p38 MAP kinase activation leads to phosphorylation of ␣BC on Ser 59 (P-␣BC-S59), which increases its protective ability. ␣BC confers protection, in part, by interacting with and affecting the functions of key components in stressed cells. We investigated the hypothesis that protection from I/R damage in the heart by P-␣BC-S59 can be mediated by localization to mitochondria. We found that P-␣BC-S59 localized to mitochondria isolated from untreated mouse hearts and that this localization increased more than threefold when the hearts were subjected to ex vivo I/R. Mitochondrial P-␣BC-S59 decreased when hearts were treated with the p38 inhibitor SB-202190. Moreover, SB-202190-treated hearts exhibited more tissue damage and less functional recovery upon reperfusion than controls. I/R activates mitochondrial permeability transition (MPT) pore opening, which increases cell damage. We found that mitochondria incubated with a recombinant mutant form of ␣BC that mimics P-␣BC-S59 exhibited decreased calcium-induced MPT pore opening. These results indicate that mitochondria may be among the key components in stressed cells with which P-␣BC-S59 interacts and that this localization may protect the myocardium, in part, by modulating MPT pore opening and, thus, reducing I/R injury. mitochondrial permeability transition; cardioprotection

show abstract

Section: Discussionsupporting

confidence: 93%

Localization of phosphorylated αB-crystallin to heart mitochondria during ischemia-reperfusion

Jin

Whittaker²,

Glassy³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Beneficial myocardial effects of α-B crystallin were previously reported in ischemia-reperfusion experiments 30,31 and attributed to interaction between α-B crystallin and titin. 16,32 Recently, the small heat shock proteins HSP27 and α-B crystallin were shown to protect cardiomyocytes against stretch-induced damage in acidic pH.…”

Section: Cardiomyocyte Stiffness and α-B Crystallinmentioning

confidence: 72%

α-B Crystallin Reverses High Diastolic Stiffness of Failing Human Cardiomyocytes

Franssen

Kole

Musters

et al. 2017

Circ: Heart Failure

View full text Add to dashboard Cite

Background-Cardiomyocytes with a less distensible titin and interstitial collagen contribute to the high diastolic stiffness of failing myocardium. Their relative contributions and mechanisms underlying loss of titin distensibility were assessed in failing human hearts. Methods and Results-Left ventricular tissue was procured in patients with aortic stenosis (AS, n=9) and dilated cardiomyopathy (DCM, n=6). Explanted donor hearts (n=8) served as controls. Stretches were performed in myocardial strips, and an extraction protocol differentiated between passive tension (F passive ) attributable to cardiomyocytes or to collagen. F passive -cardiomyocytes was higher in AS and DCM at shorter muscle lengths, whereas F passive -collagen was higher in AS at longer muscle lengths and in DCM at shorter and longer muscle lengths. Cardiomyocytes were stretched to investigate titin distensibility. Cardiomyocytes were incubated with alkaline phosphatase, subsequently reassessed after a period of prestretch and finally treated with the heat shock protein α-B crystallin. Alkaline phosphatase shifted the F passive -sarcomere length relation upward only in donor. Prestretch shifted the F passive -sarcomere length relation further upward in donor and upward in AS and DCM. α-B crystallin shifted the F passive -sarcomere length relation downward to baseline in donor and to lower than baseline in AS and DCM. In failing myocardium, confocal laser microscopy revealed α-B crystallin in subsarcolemmal aggresomes. Conclusions-High cardiomyocyte stiffness contributed to stiffness of failing human myocardium because of reduced titin distensibility. The latter resulted from an absent stiffness-lowering effect of baseline phosphorylation and from titin aggregation. High cardiomyocyte stiffness was corrected by α-B crystallin probably through relief of titin aggregation. (Circ Heart Fail. 2017;10:e003626.

show abstract

“…This model consists of beating adult cardiomyocytes loaded with calcein, a relevant marker to detect mPTP opening, subjected to 30 min of severe hypoxia in the presence of a metabolic blocker. The advantage of this model is to match optimally the conditions encountered during ischemia-reperfusion contrary to other protocols, such as permeabilization of the cellular membrane in the presence of high Ca 2ϩ concentration or exposure of cells to pro-oxidant agents, such as H 2 O 2 (Park et al, 2006) or generation of ROS generated by laser illumination (Juhaszova et al, 2004;Kadono et al, 2006). It should be noted that neither cell death nor mPTP opening could be obtained in the absence of electrical stimulation highlighting its crucial role in this model.…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective Effect of Morphine and a Blocker of Glycogen Synthase Kinase 3β, SB216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione], via Inhibition of the Mitochondrial Permeability Transition Pore

Obame¹,

Plin-Mercier²,

Assaly³

et al. 2008

J Pharmacol Exp Ther

101

View full text Add to dashboard Cite

Morphine has been shown to protect the myocardium against ischemia-reperfusion injury through inhibition of glycogen synthase kinase-3␤ (GSK-3␤). Given that GSK-3␤ is known to modulate the mitochondrial permeability transition pore (mPTP), we investigated the role of mPTP in the cardioprotective effect of morphine and the GSK-3␤ inhibitor SB216763 [SB; 3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] during ischemia-reperfusion. Both morphine (0.3 mg/kg) and SB (0.6 mg/kg) reduced infarct size in a model of regional myocardial ischemia-reperfusion in rats (13 Ϯ 1 and 14 Ϯ 3% of the area at risk versus 33 Ϯ 4% in controls; p Ͻ 0.05). Morphine and SB protected the ischemic myocardium against Ca 2ϩ -induced mPTP opening as demonstrated by the increased capacity of mitochondria to retain Ca 2ϩ when they were isolated from the ischemic zone 10 min after the onset of reperfusion (59 Ϯ 8 and 66 Ϯ 3 versus 29.5 Ϯ 6 nmol Ca 2ϩ /mg ⅐ protein, respectively; p Ͻ 0.05). This was associated with a restoration of mitochondrial oxidative phosphorylation parameters. In isolated adult rat cardiomyocytes subjected to anoxiareoxygenation, morphine (2 M), SB (3 M), and the direct mPTP inhibitor cyclosporine A (3 M) delayed mPTP opening as assessed by the calcein loading Co 2ϩ -quenching technique. This was accompanied by an increase in cell survival as measured by nuclear staining with propidium iodide. These in vitro effects of morphine on inhibition of mPTP opening during anoxia-reoxygenation were suppressed by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor wortmannin (0.1 M). These data indicate that the infarct-limiting effect of morphine and SB is linked by a cause-effect relationship, which leads to an increased mitochondrial resistance and inhibition of mPTP opening through the PI3-kinase pathway and subsequent inactivation of GSK-3␤.There are many investigations that suggest that the opening of mitochondrial permeability transition pore (mPTP) is involved in myocardial ischemia-reperfusion injury (Di Lisa and Bernardi, 2006;Halestrap, 2006;Javadov and Karmazyn, 2007) and that raising the threshold for mPTP opening is a relevant strategy to provide cardioprotection (Tissier et al., 2008).

show abstract

CRYAB and HSPB2 deficiency increases myocyte mitochondrial permeability transition and mitochondrial calcium uptake

Cited by 41 publications

References 23 publications

Localization of phosphorylated αB-crystallin to heart mitochondria during ischemia-reperfusion

Localization of phosphorylated αB-crystallin to heart mitochondria during ischemia-reperfusion

α-B Crystallin Reverses High Diastolic Stiffness of Failing Human Cardiomyocytes

Cardioprotective Effect of Morphine and a Blocker of Glycogen Synthase Kinase 3β, SB216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione], via Inhibition of the Mitochondrial Permeability Transition Pore

Contact Info

Product

Resources

About