The Effect of Myocardial Infarct Size on Cardiac Reserve in Rhesus Monkeys

Cai, Jindan; Sun, Xiaorong; Han, Ping; Xiao, Ying; Fan, Xin; Shang, Yanan; Kang, Y. James

doi:10.1007/s12012-014-9253-3

Cited by 7 publications

(5 citation statements)

References 36 publications

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“…As described in our previous studies, 14,15 the heart of monkeys was exposed via the left fourth intercostal thoracotomy. The LAD artery was occluded for 1 min followed by a 5 min reperfusion, and this occlusion-reperfusion cycle was repeated 3 times before the eventual ligation.…”

Section: Induction Of Myocardial Ischemic Infarctionmentioning

confidence: 99%

“…12 Our recent studies demonstrated that the Rhesus monkey model of myocardial ischemic infarction recaptured the manifestations in human myocardial infarction. [13][14][15] The present study was undertaken employing a Rhesus monkey model of myocardial ischemia induced by left anterior descending (LAD) artery ligation to examine the relationship between the changes in HIF-1 and its regulated gene expression and the depressed capillary density following a long-term ischemia.…”

Section: Introductionmentioning

confidence: 99%

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The association of depressed angiogenic factors with reduced capillary density in the Rhesus monkey model of myocardial ischemia

et al. 2016

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Depressed capillary density is associated with myocardial ischemic infarction, in which hypoxia-inducible factor 1α (HIF-1α) is increased. The present study was undertaken to examine changes in the angiogenic factors whose expression is regulated by HIF-1 and their relation to the depressed capillary density in the Rhesus monkey model of myocardial ischemic infarction. Male Rhesus monkeys 2-3 years old were subjected to myocardial ischemia by permanent ligation of left anterior descending (LAD) artery leading to the development of myocardial infarction. Eight weeks after LAD ligation, copper concentrations, myocardial histological changes and capillary density were examined, along with Western blot and immunohistochemical analysis of angiogenic factors and detection of HIF-1 activity. Capillary density was significantly decreased but the concentrations of HIF-1α and HIF-1β were significantly increased in the infarct area. However, the levels of mRNA and protein for VEGF and VEGFR1 were significantly decreased. Other HIF-1 regulated angiogenic factors, including Tie-2, Ang-1 and FGF-1, were also significantly depressed, but vascular destabilizing factor Ang-2 was significantly increased. Copper concentrations were depressed in the infarct area. Copper-independent HIF-1 activity was increased shown by the elevated mRNA level of IGF-2, a HIF-1 target gene. Removal of copper by a copper chelator, tetraethylenepentamine, from primary cultures of neonatal rat cardiomyocytes also suppressed the expression of HIF-1 regulated VEGF and BNIP3, but not IGF-2. The data suggest that under ischemic conditions, copper loss suppressed the expression of critical angiogenic genes regulated by HIF-1, but did not affect copper-independent HIF-1 activation of gene expression. This copper-dependent dysregulation of angiogenic gene expression would contribute to the pathogenesis of myocardial ischemic infarction.

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Section: Induction Of Myocardial Ischemic Infarctionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The association of depressed angiogenic factors with reduced capillary density in the Rhesus monkey model of myocardial ischemia

et al. 2016

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“…As described in our previous studies [ 27 , 28 ], the monkey’s heart was exposed via a left fourth intercostal thoracotomy incision (4–5 cm) in the chest wall. The LAD was occluded for 1 min followed by a 5 min reperfusion, and this occlusion-reperfusion cycle was repeated 3 times before the eventual permanent ligation.…”

Section: Methodsmentioning

confidence: 99%

Dynamic regulation of HIF-1 signaling in the rhesus monkey heart after ischemic injury

Wang

Xiao

Zhang

et al. 2022

BMC Cardiovasc Disord

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Background Hypoxia inducible factor-1 (HIF-1) plays a key role in modulating post-infarct healing after myocardial ischemic injury through transcriptional regulation of hundreds of genes involved in diverse cardiac remodeling processes. However, the dynamic changes in HIF-1 target gene expression in the ischemic heart after myocardial infarction (MI) have not been well characterized. Methods We employed a rhesus monkey model of MI induced by left anterior descending artery ligation and examined the expression pattern of HIF-1 target genes in the ischemic heart at 1, 7, and 28 days after injury by bulk RNA-sequencing analysis. Results Myocardial transcriptomic analysis demonstrated a temporal-specific regulation of genes associated with the inflammatory response, cell proliferation, fibrosis and mitochondrial metabolism during the pathological progression of MI. HIF-1 target genes involved in processes related to glycolysis, angiogenesis, and extracellular matrix (ECM) remodeling also exhibited distinct expression patterns during MI progression. Copper concentrations were gradually decreased in the heart after ischemic injury, which was positively correlated with the expression of HIF-1-mediated angiogenic and glycolytic genes but negatively correlated with the expression of HIF-1-mediated ECM remodeling genes. Moreover, genes related to intracellular copper trafficking and storage were suppressed along with the loss of myocardial copper in the ischemic heart. Conclusions This study demonstrated a dynamic, functional-specific regulation of HIF-1 target gene expression during the progression of MI. The fine-tuning of HIF-1 signaling in the ischemic heart may be relate to the alteration in myocardial copper homeostasis. These findings provide transcriptomic insights into the distinct roles of HIF-1 signaling in the heart after ischemic injury, which will help determine the beneficial cutoff point for HIF-1 targeted therapy in ischemic heart diseases.

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“…It is obvious that ligation at different levels along the LAD artery will differentially affect areas of the left ventricle. (7,15) What's more important, the LAD artery is branched, quite different from rodents. It is particularly noticed that blood vessels branched from the LAD artery in monkeys display an irregular distribution, thus affecting the consistency of ischemic infarction area of the ventricle.…”

Section: Introductionmentioning

confidence: 99%

An improved monkey model of myocardial ischemic infarction for cardiovascular drug development

Wang,

Han,

Huang

et al. 2022

Preprint

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Non-human primate monkey model of myocardial ischemic infarction is precious for translational medicine research. Ligation of the left anterior descending (LAD) artery is the effective way to induce myocardial ischemic infarction. However, the consistency of the myocardial infarction thus generated remains problematic. The present study was undertaken to critically evaluate the monkey model of myocardial ischemic infarction to develop a procedure for a consistent cross-studies comparison. Forty male Rhesus monkeys were divided into 4 groups and subjected to LAD artery ligation at different levels along the artery. In addition, the major diagonal branch was selectively ligated parallel to the ligation site of the LAD artery according to the diagonal branch distribution. Analyses of MRI, echocardiography, cardiac hemodynamics, electrocardiography, histopathology, and cardiac injury biomarkers were undertaken to characterize the structural and functional alterations of monkeys with myocardial infarction. Ligation at 40% of the total length of the artery, measured from the apex end, produced variable infarct areas with inconsistent functional alterations. Ligation at 60% or above coupled with selective ligation of diagonal branches produced consistent myocardial infarction with uniformed dysfunction. However, ligation at 70% caused a lethal threat. After a thorough analysis, it is concluded that ligation at 60% of the total length coupled with selective ligation of diagonal branches, which enables standardization of the location of occlusion and the subsequent ischemic area, as well as avoids the influence of the diagonal branches, are ideal to produce a consistent monkey model of myocardial ischemic infarction.

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The Effect of Myocardial Infarct Size on Cardiac Reserve in Rhesus Monkeys

Cited by 7 publications

References 36 publications

The association of depressed angiogenic factors with reduced capillary density in the Rhesus monkey model of myocardial ischemia

The association of depressed angiogenic factors with reduced capillary density in the Rhesus monkey model of myocardial ischemia

Dynamic regulation of HIF-1 signaling in the rhesus monkey heart after ischemic injury

An improved monkey model of myocardial ischemic infarction for cardiovascular drug development

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