Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection

Zheng, Jingang; Chin, Andrew I.; Duignan, Inga; Won, Kyung-Heon; Hong, Mun K.; Edelberg, Jay M.

doi:10.1152/ajpheart.00470.2005

Cited by 19 publications

(10 citation statements)

References 29 publications

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“…The cardioprotective effect of ischemic pre-and postconditioning is inhibited by several comorbid conditions and risk factors such as aging (3,47,59), hyperlipidemia (14 -17, 23, 36, 55), and diabetes (35,48,54). However, recent evidence suggests that the cardioprotective effect of pre-and postconditioning is maintained in subacute renal failure (4 wk) (4) and short-term (10 wk) (32) model of uremia.…”

Section: Discussionmentioning

confidence: 99%

Preconditioning protects the heart in a prolonged uremic condition

Kocsis

Sárközy

Bencsik

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Metabolic diseases such as hyperlipidemia and diabetes attenuate the cardioprotective effect of ischemic preconditioning. In the present study, we examined whether another metabolic disease, prolonged uremia, affects ischemia/reperfusion injury and cardioprotection by ischemic preconditioning. Uremia was induced by partial nephrectomy in male Wistar rats. The development of uremia was verified 29 wk after surgery. Transthoracic echocardiography was performed to monitor cardiac function. At week 30, hearts of nephrectomized and sham-operated rats were isolated and subjected to a 30-min coronary occlusion followed by 120 min reperfusion with or without preceding preconditioning induced by three intermittent cycles of brief ischemia and reperfusion. In nephrectomized rats, plasma uric acid, carbamide, and creatinine as well as urine protein levels were increased as compared with shamoperated controls. Systolic anterior and septal wall thicknesses were increased in nephrectomized rats, suggesting the development of a minimal cardiac hypertrophy. Ejection fraction was decreased and isovolumic relaxation time was shortened in nephrectomized rats demonstrating a mild systolic and diastolic dysfunction. Infarct size was not affected significantly by nephrectomy itself. Ischemic preconditioning significantly decreased infarct size from 24.8 Ϯ 5.2% to 6.6 Ϯ 1.3% in the sham-operated group and also in the uremic group from 35.4 Ϯ 9.5% to 11.9 Ϯ 3.1% of the area at risk. Plasma ANG II and nitrotyrosine were significantly increased in the uremic rats. We conclude that although prolonged experimental uremia leads to severe metabolic changes and the development of a mild myocardial dysfunction, the cardioprotective effect of ischemic preconditioning is still preserved. chronic renal failure; myocardium; ischemic preconditioning; infarct size; myocardial function ISCHEMIC PRECONDITIONING IS a well-characterized endogenous adaptive response of the myocardium in which brief cycles of ischemia markedly enhance the ability of the heart to withstand a subsequent ischemic injury (15). Although preconditioning confers remarkable cardioprotection in a variety of species (15, 44), including humans (21, 49, 55), we and others have shown that its effectiveness is attenuated by some risk factors and comorbidities such as metabolic diseases including hyperlipidemia (14 -16) and diabetes (35, 54) both in animal models and humans (15).

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Section: Discussionmentioning

confidence: 99%

Preconditioning protects the heart in a prolonged uremic condition

Kocsis

Sárközy

Bencsik

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…Focusing on in vivo studies, IP's cardioprotection was preserved in 4-yr-old rabbits and 5.7-to 8-yr-old sheep (31), whereas IP's cardioprotection was impaired in the senescent rat heart (24 mo old; see Ref. 43). Our study is the first in which IP's cardioprotection was analyzed in the aged mouse heart in situ, and, in contrast to young hearts, IP is ineffective at an age Ͼ13 mo.…”

Section: Discussionmentioning

confidence: 99%

Loss of ischemic preconditioning's cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43

Boengler

Konietzka²,

Buechert³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

164

104

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Boengler K, Konietzka I, Buechert A, Heinen Y, Garcia-Dorado D, Heusch G, Schulz R. Loss of ischemic preconditioning's cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43. Am J Physiol Heart Circ Physiol 292: H1764 -H1769, 2007. First published December 1, 2006; doi:10.1152/ajpheart.01071.2006 is localized at left ventricular (LV) gap junctions and in cardiomyocyte mitochondria. A genetically induced reduction of Cx43 as well as blockade of mitochondrial Cx43 import abolishes the infarct size (IS) reduction by ischemic preconditioning (IP). With progressing age, Cx43 content in ventricular and atrial tissue homogenates is reduced. We now investigated whether or not 1) the mitochondrial Cx43 content is reduced in aged mice hearts and 2) IS reduction by IP is lost in aged mice hearts in vivo. Confirming previous results, sarcolemmal Cx43 content was reduced in aged (Ͼ13 mo) compared with young (Ͻ3 mo) C57Bl/6 mice hearts, whereas the expression levels of protein kinase C ⑀ and endothelial nitric oxide synthase remained unchanged. Also in mitochondria isolated from aged mice LV myocardium, Western blot analysis indicated a 40% decrease in Cx43 content compared with mitochondria isolated from young mice hearts. In young mice hearts, IP by one cycle of 10 min ischemia and 10 min reperfusion reduced IS (% of area at risk) following 30 min regional ischemia and 120 min reperfusion from 67.7 Ϯ 3.3 (n ϭ 17) to 34.2 Ϯ 6.6 (n ϭ 5, P Ͻ 0.05). In contrast, IP's cardioprotection was lost in aged mice hearts, since IS in nonpreconditioned (57.5 Ϯ 4.0, n ϭ 10) and preconditioned hearts (65.4 Ϯ 6.3, n ϭ 8, P ϭ not significant) was not different. In conclusion, mitochondrial Cx43 content is decreased in aged mouse hearts. The reduced levels of Cx43 may contribute to the age-related loss of cardioprotection by IP. left ventricle; infarct size; translocase of the outer membrane 20 BRIEF PERIODS OF ischemia-reperfusion delay the development of cell death from a subsequent prolonged episode of ischemiareperfusion, a phenomenom known as ischemic preconditioning (IP; for review see Refs. 10 and 34). Connexin 43 (Cx43) is essential for cardioprotection (36). The cardioprotection by ischemic or pharmacological preconditioning with diazoxide is abolished both in in situ hearts and in isolated cardiomyocytes from heterozygous Cx43-deficient mice (17,23,37). Apart from its localization at the sarcolemma, Cx43 is also detected at the inner membrane of cardiomyocyte mitochondria (3, 32), i.e., in cell organelles that are central for triggering/mediating the cardioprotection by IP (21,26,28). Indeed, the reduction of mitochondrial Cx43 by geldanamycin, which inhibits heat shock protein 90 and thereby decreases the translocation of Cx43 to the mitochondria, abolishes the infarct size reduction by diazoxide otherwise seen in isolated rat hearts (32).Reactive oxygen species (ROS), which are partially produced by uncoupling of oxidative phosphorylation, trigger IP's cardioprotecti...

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“…However, the results on the effectiveness of ischemic preconditioning in the aged myocardium remain controversial (for a detailed review of in vitro studies, see Juhaszova et al, 2005). With a focusing on in vivo studies, ischemic preconditioning-induced cardioprotection was preserved in 4-year-old rabbits and 5-to 8-year-old sheep (Burns et 446 al., 1996;Przyklenk et al, 2001), whereas cardioprotection by ischemic preconditioning was impaired in senescent rat (24 months old) (Zheng et al, 2006) and mouse (13-16 months old) hearts (Boengler et al, , 2007b.…”

Section: E Aging and Cardioprotectionmentioning

confidence: 99%