On Mice, Rabbits, and Human Heart Failure

Marian, Ali J.

doi:10.1161/01.cir.0000167559.13502.9a

Cited by 29 publications

(17 citation statements)

References 28 publications

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“…Dexrazoxane, as a positive control, was previously capable of affording effective cardioprotection in our model that again supports its relevance. Furthermore, it was recently pointed out that, in rabbits, the cardiomyo- cyte calcium handling and structure and function of myocardial sarcomere reflect, both in normal and failing heart, the human system more accurately than in rodents (Marian, 2005).…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective Effects of a Novel Iron Chelator, Pyridoxal 2-Chlorobenzoyl Hydrazone, in the Rabbit Model of Daunorubicin-Induced Cardiotoxicity

Štěrba

Popelová

Šimůnek

et al. 2006

J Pharmacol Exp Ther

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Iron chelation is the only pharmacological intervention against anthracycline cardiotoxicity whose effectiveness has been well documented both experimentally and clinically. In this study, we aimed to assess whether pyridoxal 2-chlorobenzoyl hydrazone (o-108, a strong iron chelator) can provide effective protection against daunorubicin (DAU)-induced chronic cardiotoxicity in rabbits. First, using the HL-60 leukemic cell line, it was shown that o-108 has no potential to blunt the antiproliferative efficacy of DAU. Instead, o-108 itself moderately inhibited cell proliferation. In vivo, chronic DAU treatment (3 mg/kg weekly for 10 weeks) induced mortality (33%), left ventricular (LV) dysfunction, a troponin T rise, and typical morphological LV damage. In contrast, all animals treated with 10 mg/kg o-108 before DAU survived without a significant drop in the LV ejection fraction (63.2 Ϯ 0.5 versus 59.2 Ϯ 1.0%, beginning versus end, not significant), and their cardiac contractility (dP/dt max ) was significantly higher than in the DAU-only group (1131 Ϯ 125 versus 783 Ϯ 53 kPa/s, p Ͻ 0.05), which corresponded with histologically assessed lower extent and intensity of myocardial damage. Although higher o-108 dose (25 mg/kg) was well tolerated when administered alone, in combination with DAU it led to rather paradoxical and mostly negative results regarding both cardioprotection and overall mortality. In conclusion, we show that shielding of free intracellular iron using a potent lipophilic iron chelator is able to offer a meaningful protection against chronic anthracycline cardiotoxicity. However, this approach lost its potential with the higher chelator dose, which suggests that iron might play more complex role in the pathogenesis of this disease than previously assumed.

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Section: Discussionmentioning

confidence: 99%

Cardioprotective Effects of a Novel Iron Chelator, Pyridoxal 2-Chlorobenzoyl Hydrazone, in the Rabbit Model of Daunorubicin-Induced Cardiotoxicity

Štěrba

Popelová

Šimůnek

et al. 2006

J Pharmacol Exp Ther

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“…The lower power in turn contributes to depressed systolic function in end-stage heart failure (Stelzer et al, 2007). While MyHC-α decreases in failing hearts, it increases with recovery (Haworth, 2007), and may be cardioprotective in stressed myocardium (Marian, 2005). In dilated rabbit hearts with tachycardia-induced cardiomyopathy, transgenic expression of MyHC-α was cardioprotective (James et al, 2005).…”

Section: Cardiac Myosin Isoform Expression In Ground Squirrelsmentioning

confidence: 99%

Increase in cardiac myosin heavy-chain (MyHC) alpha protein isoform in hibernating ground squirrels, with echocardiographic visualization of ventricular wall hypertrophy and prolonged contraction.

Nelson

Rourke

2013

Journal of Experimental Biology

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SUMMARYDeep hibernators such as golden-mantled ground squirrels (Callospermophilus lateralis) have multiple challenges to cardiac function during low temperature torpor and subsequent arousals. As heart rates fall from over 300 beats min -1 to less than 10, chamber dilation and reduced cardiac output could lead to congestive myopathy. We performed echocardiography on a cohort of individuals prior to and after several months of hibernation. The left ventricular chamber exhibited eccentric and concentric hypertrophy during hibernation and thus calculated ventricular mass was ~30% greater. Ventricular ejection fraction was mildly reduced during hibernation but stroke volumes were greater due to the eccentric hypertrophy and dramatically increased diastolic filling volumes. Globally, the systolic phase in hibernation was ~9.5 times longer, and the diastolic phase was 28× longer. Left atrial ejection generally was not observed during hibernation. Atrial ejection returned weakly during early arousal. Strain echocardiography assessed the velocity and total movement distance of contraction and relaxation for regional ventricular segments in active and early arousal states. Myocardial systolic strain during early arousal was significantly greater than the active state, indicating greater total contractile movement. This mirrored the increased ventricular ejection fraction noted with early arousal. However, strain rates were slower during early arousal than during the active period, particularly systolic strain, which was 33% of active, compared with the rate of diastolic strain, which was 67% of active. As heart rate rose during the arousal period, myocardial velocities and strain rates also increased; this was matched closely by cardiac output. Curiously, though heart rates were only 26% of active heart rates during early arousal, the cardiac output was nearly 40% of the active state, suggesting an efficient pumping system. We further analyzed proportions of cardiac myosin heavy-chain (MyHC) isoforms in a separate cohort of squirrels over 5 months, including time points before hibernation, during hibernation and just prior to emergence. Hibernating individuals were maintained in both a 4°C cold room and a 20°C warm room. Measured by SDS-PAGE, relative percentages of cardiac MyHC alpha were increased during hibernation, at both hibernacula temperatures. A potential increase in contractile speed, and power, from more abundant MyHC alpha may aid force generation at low temperature and at low heart rates. Unlike many models of cardiomyopathies where the alpha isoform is replaced by the beta isoform in order to reduce oxygen consumption, ground squirrels demonstrate a potential cardioprotective mechanism to maintain cardiac output during torpor. Received 25 March 2013; Accepted 4 September 2013Key words: hibernation, MyHC, echocardiogram, atrial contraction, cardiac function. Echocardiogram and myosin of hibernatorsThe myosin heavy-chain isoforms (MyHC) are crucial determinants of contractile performance in cardiac muscle t...

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“…29,30 In the study of heart failure, the choice of the rabbit as the transgenic model is also commendable because the rabbit heart has a sarcomeric protein composition more similar to that of the human heart and the length of the contractile cycle is significantly longer. 31 In addition, whereas rabbits are similar to mice in lacking apo(a) and lipoprotein(a), their lipoprotein profile more closely mimics that of humans, with low-density lipoprotein as the predominant plasma lipoprotein. When fed a cholesterol-rich diet, rabbits develop wellcharacterized humanlike atherosclerotic lesions, which can be induced to rupture as well.…”

Section: Article P 1993mentioning

confidence: 98%

Novel Transgenic Rabbit Model Sheds Light on the Puzzling Role of Matrix Metalloproteinase-12 in Atherosclerosis

2006

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M atrix metalloproteinases (MMPs), also termed matrixins, are known to affect atherosclerosis in many diverse ways. [1][2][3] Apart from a role in the progression of atherosclerotic lesions, MMPs have also been involved in plaque destabilization and rupture and in the development of aneurysms. Despite intense research efforts during the last decade, it has been challenging to formulate a unifying model on the specific role of MMPs in atherosclerosis. In fact, mouse genetic studies have yielded controversial insights, highly dependent on genetic background, dietary regimen, and arterial site of analysis, whereas human genetic association studies do not prove causality of MMPs in atherosclerosis. Moreover, the lack of specific inhibitors precluded pharmacological dissection of the role of MMPs in vivo. There is thus a need for alternative strategies to decipher the MMP puzzle in atherosclerosis. In this issue of Circulation, Liang et al 4 used a novel approach: They generated transgenic rabbits to study the role of MMP-12, also known as macrophage elastase, in atherosclerosis. Their results indicate that MMP-12 causes media destruction and pseudoaneurysm formation and, more surprisingly, accelerates plaque growth in an animal model that more closely resembles atherosclerosis in humans. Article p 1993MMPs belong to one of the most ancient families of enzymes that arose in evolution soon after the first signs of life to regulate, in general, interactions of cells with the extracellular matrix (ECM). To cope with this formidable challenge, more than 65 structurally related MMPs developed in bacteria, plants, nematodes, fruit flies, sea urchins, and vertebrates. One of their key activities is breaking down ECM substrates in the basement membrane and interstitial matrix. 1,2 As such, MMPs facilitate migration of macrophages and smooth muscle cells (SMCs) in atherosclerotic plaques by degrading ECM barriers, exposing novel ECM adhesion sites, and relieving the binding between basement membrane components and cell surface integrins that restrains movement. In addition, detachment of SMCs from its basement membrane and generation of ECM degradation products may induce proliferation, migration, and a switch to a synthetic phenotype. Of all MMPs, MMP-12 evolved as the most active elastase; its hemopexin-like domain diverged into a separate subfamily, more specialized in the binding of elastin than the corresponding substrate binding domains of other MMPs.Apart from degrading ECM proteins, MMPs also acquired many other functions during evolution by broadening their substrate specificity. Other MMPs are capable of regulating the recruitment of inflammatory cells and the growth of SMCs and endothelial cells in plaques by liberating growth factors sequestered in the ECM (fibroblast growth factor-2, transforming growth factor-␤, vascular endothelial growth factor, and others). 1,3 By disrupting CD44 and cadherins and causing shedding of selectins, MMPs may modulate vascular and inflammatory cell migration. Apart from the fact th...

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On Mice, Rabbits, and Human Heart Failure

Cited by 29 publications

References 28 publications

Cardioprotective Effects of a Novel Iron Chelator, Pyridoxal 2-Chlorobenzoyl Hydrazone, in the Rabbit Model of Daunorubicin-Induced Cardiotoxicity

Cardioprotective Effects of a Novel Iron Chelator, Pyridoxal 2-Chlorobenzoyl Hydrazone, in the Rabbit Model of Daunorubicin-Induced Cardiotoxicity

Increase in cardiac myosin heavy-chain (MyHC) alpha protein isoform in hibernating ground squirrels, with echocardiographic visualization of ventricular wall hypertrophy and prolonged contraction.

Novel Transgenic Rabbit Model Sheds Light on the Puzzling Role of Matrix Metalloproteinase-12 in Atherosclerosis

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