Preconditioning limits myocardial infarct size in hypercholesterolemic rabbits

Kremastinos, Dimitrios Th.; Bofilis, Elias; Karavolias, George; Papalois, Apostolos; Kaklamanis, Loukas; Iliodromitis, Efstathios K.

doi:10.1016/s0021-9150(99)00389-5

Cited by 46 publications

(37 citation statements)

References 28 publications

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“…Moreover, Juhasz et al (2004) found a significant increase in infarct size in preconditioned hyperlipidemic rabbits compared with nonpreconditioned ischemic control. In contrast to these studies, in apolipoprotein E/low-density lipoprotein receptor doubleknockout mice fed a 0.15% cholesterol-and 21% fat-enriched diet for 8 months (Li et al, 2001) or in rabbits fed a cholesterol-enriched diet for 8 weeks (Kremastinos et al, 2000) or cholesterol-and coconut oil-rich chow for 4 weeks (Jung et al, 2000), the infarct size-limiting effect of preconditioning was preserved. The discrepancies can be attributed to substantial differences in experimental hyperlipidemia (species, duration, and composition of diet) leading to differences in the severity of coronary atherosclerosis.…”

Section: Discussionmentioning

confidence: 66%

Hyperlipidemia Attenuates the Infarct Size-Limiting Effect of Ischemic Preconditioning: Role of Matrix Metalloproteinase-2 Inhibition

Giricz¹,

Lalu²,

Csonka³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

100

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Hyperlipidemia attenuates the cardioprotective effect of preconditioning via unknown mechanisms. We have reported previously that in normolipidemic rats, preconditioning decreased ischemia-induced activation and release of myocardial matrix metalloproteinase (MMP)-2 into the coronary perfusate. Here, we investigated whether hyperlipidemia interferes with the cardioprotective effect of preconditioning through modulation of MMP-2. Hearts isolated from male Wistar rats fed 2% cholesterol-enriched or control chow for 9 weeks were subjected to a preconditioning protocol (three intermittent periods of ischemia/reperfusion of 5-min duration each) or a time-matched nonpreconditioning protocol. This was followed by a test ischemia/reperfusion (30-min ischemia and 120-min reperfusion) in both groups. Preconditioning decreased infarct size in the control but not the cholesterol-fed group. Cardioprotection in the preconditioned control group but not in the cholesterol-fed group was associated with an 18 Ϯ 3% (p Ͻ 0.05) inhibition of test ischemia/reperfusion-induced activation and release of myocardial MMP-2 into the perfusate. Myocardial protein levels of tissue inhibitors of MMPs [tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4] were not changed in either group. A reduction of infarct size in nonpreconditioned hearts from both control and cholesterol-fed group was produced by the MMP inhibitor ilomastat at 0.25 M, a concentration producing MMP-2 inhibition comparable with that of preconditioning in the control group. We conclude that hyperlipidemia blocks preconditioning-induced cardioprotection, hyperlipidemia abolishes preconditioning-induced inhibition of myocardial MMP-2 activation and release, preconditioning-induced inhibition of MMP-2 activation and release is not mediated by TIMPs, and pharmacological inhibition of MMPs produces cardioprotection in both normal and hyperlipidemic rats.Ischemic preconditioning is a well described adaptive response in which brief exposure to ischemia markedly enhances the ability of the heart to withstand a subsequent ischemic injury (for review, see Baxter and Ferdinandy, 2001;Yellon and Downey, 2003). Although preconditioning confers remarkable cardioprotection in a variety of species, including humans, it seems that its effectiveness is attenuated in several disease states such as hyperlipidemia, diabetes, heart failure, nitrate tolerance, etc. (for review, see Ferdinandy et al., 1998b;Ferdinandy, 2003).Although most studies show that hyperlipidemia inhibits the cardioprotective effect of preconditioning (when looking at endpoints such as ST segment elevation or cardiac function), there is a controversy whether the infarct size-limiting effect of preconditioning is lost in hyperlipidemia or not (for review, see Ferdinandy, 2003). The discrepancies can be attributed to the substantial differences in hyperlipidemia models (species, duration of hyperlipidemic diet, presence of significant coronary sclerosis). Therefore, here we have used hearts of male Wistar rats ...

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Section: Discussionmentioning

confidence: 66%

Hyperlipidemia Attenuates the Infarct Size-Limiting Effect of Ischemic Preconditioning: Role of Matrix Metalloproteinase-2 Inhibition

Giricz¹,

Lalu²,

Csonka³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

100

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“…In one of these clinical studies, the loss of the anti-ischemic effect of early preconditioning was correlated with increased plasma cholesterol and LDL levels (Kyriakides et al, 2002). In contrast to the aforementioned studies, in rabbits fed a cholesterol-enriched diet for 8 weeks (Kremastinos et al, 2000), 6 weeks (Iliodromitis et al, 2006b), or 4 weeks (Jung et al, 2000) and in severely atherosclerotic ApoE/LDLr Ϫ/Ϫ double knockout mice fed an atherogenic diet for 6 to 8 months ) and 7 to 9 months (Tokuno et al, 2002) the infarct sizelimiting effect of classic preconditioning was not attenuated. The reasons for these conflicting results are unknown, but it seems that in some hyperlipidemic models the presence of severe atherosclerosis and the resultant alterations in liver function may further affect the complex pathophysiology of hyperlipidemia and mechanisms of adaptive cardioprotection.…”

Section: Cardioprotection By Pre-and Postconditioning In Hyperlipidemiamentioning

confidence: 99%

Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning

Ferdinándy¹,

Schulz²,

Baxter³

2007

Pharmacological Reviews

652

615

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“…While Giricz et al (66) confirmed that hyperlipidemia eliminates protection with Precon in rats (an effect potentially related to dysregulation of matrix metalloproteinase-2), Jung et al (105) and Kremastinos et al (121) reported that hypercholesterolemia does not negate Precon in rabbits. Nonetheless, intrinsic tolerance to I/R was found to be reduced in the study of Jung et al (105).…”

Section: Age and Disease Dependence Of Cardioprotectionmentioning

confidence: 99%

Clinical cardioprotection and the value of conditioning responses

Peart

Headrick²

2009

American Journal of Physiology-Heart and Circulatory Physiology

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Adjunctive cardioprotective strategies for ameliorating the reversible and irreversible injuries with ischemia-reperfusion (I/R) are highly desirable. However, after decades of research, the promise of clinical cardioprotection from I/R injury remains poorly realized. This may arise from the challenges of trialing and effectively translating experimental findings from laboratory models to patients. One can additionally consider whether features of the more heavily focused upon candidates could limit or preclude therapeutic utility and thus whether we might shift attention to alternate strategies. The phenomena of preconditioning and postconditioning have proven fertile in identification of experimental means of cardioprotection and are the most intensely interrogated responses in the field. However, there is evidence these processes, which share common molecular signaling elements and end effectors, may be poor choices for clinical exploitation. This includes evidence of age dependence, limiting efficacy in target aged or senescent hearts; refractoriness to conditioning stimuli in diseased myocardium; interference from a variety of relevant pharmaceuticals; inadvertent induction of these responses by prior ischemia or commonly used drugs, precluding further benefit; and sex dependence of protective signaling. This review focuses on these features, raising questions about current research strategies, and the suitability of these widely studied phenomena as rational candidates for clinical translation.

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Preconditioning limits myocardial infarct size in hypercholesterolemic rabbits

Cited by 46 publications

References 28 publications

Hyperlipidemia Attenuates the Infarct Size-Limiting Effect of Ischemic Preconditioning: Role of Matrix Metalloproteinase-2 Inhibition

Hyperlipidemia Attenuates the Infarct Size-Limiting Effect of Ischemic Preconditioning: Role of Matrix Metalloproteinase-2 Inhibition

Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning

Clinical cardioprotection and the value of conditioning responses

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