Alterations in Myofilament Function Contribute to Left Ventricular Dysfunction in Pigs Early After Myocardial Infarction

Velden, Jolanda van der; Merkus, Daphne; James, Adam; Boontje, Nicky M.; Dekkers, Dick H. W.; Stienen, G. J. M.; Lamers, Jos M. J.; Duncker, Dirk J.

doi:10.1161/01.res.0000149531.02904.09

Cited by 113 publications

(150 citation statements)

References 66 publications

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“…16,17 2D ejection fraction was calculated as (EDA − ESA)/EDA × 100%. Also, blood samples were taken from the aorta and collected in EDTA anticoagulation tubes, centrifuged, and plasma was stored at − 80°C until further analysis.…”

Section: Surgerymentioning

confidence: 99%

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

Uitterdijk

Hermans

Wijs-Meijler

et al. 2016

Laboratory Investigation

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Modulation of Wnt/Frizzled signaling with UM206 reduced infarct expansion and prevented heart failure development in mice, an effect that was accompanied by increased myofibroblast presence in the infarct, suggesting that Wnt/Frizzled signaling has a key role in cardiac remodeling following myocardial infarction (MI). This study investigated the effects of modulation of Wnt/Frizzled signaling with UM206 in a swine model of reperfused MI. For this purpose, seven swine with MI were treated with continuous infusion of UM206 for 5 weeks. Six control swine were treated with vehicle. Another eight swine were sham-operated. Cardiac function was determined by echo in awake swine. Infarct mass was estimated at baseline by heart-specific fatty acid-binding protein ELISA and at follow-up using planimetry. Components of Wnt/Frizzled signaling, myofibroblast presence, and extracellular matrix were measured at follow-up with qPCR and/or histology. Results show that UM206 treatment resulted in a significant decrease in infarct mass compared with baseline (−41 ± 10%), whereas infarct mass remained stable in the Control-MI group (+3 ± 17%). Progressive dilation of the left ventricle occurred in the Control-MI group between 3 and 5 weeks after MI, while adverse remodeling was halted in the UM206-treated group. mRNA expression for Frizzled-4 and the Frizzled co-receptor LRP5 was increased in UM206-treated swine as compared with Control-MI swine. Myofibroblast presence was significantly lower in infarcted tissue of the UM206-treated animals (1.53 ± 0.43% vs 3.38 ± 0.61%) at 5 weeks follow-up. This study demonstrates that UM206 treatment attenuates adverse remodeling in a swine model of reperfused MI, indicating that Wnt/Frizzled signaling is a promising target to improve infarct healing and limit post-MI remodeling. Although left ventricular (LV) remodeling after myocardial infarction (MI) is aimed at maintaining cardiac pump function, initial infarct size, and the subsequent progressive expansion and thinning of the infarcted area constitute the main risk factors for the development of post-MI heart failure. 1 Several strategies that influence either the infarct size and/or the ensuing process of LV remodeling have been proposed as potential therapies to halt the development and progression of LV dysfunction. 2,3 Cardiac fibroblasts, which account for up to 70% of the cells present in the myocardium, regulate extracellular matrix (ECM) turnover, and have an essential role in cardiac homeostasis. Fibroblasts are more resistant to ischemia than cardiomyocytes, 4-6 and prolonged myocardial ischemia results in death of particularly the cardiomyocytes, whereas the fibroblasts survive. Fibroblasts have therefore been proposed to be a therapeutic target to influence the healing process of the infarcted myocardium. 1,5,[7][8][9] In addition to these resident fibroblasts, fibroblasts enter the infarcted tissue by migration. When present in the infarcted area, the fibroblasts gradually differentiate into their more contractile and synthetic...

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Section: Surgerymentioning

confidence: 99%

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

Uitterdijk

Hermans

Wijs-Meijler

et al. 2016

Laboratory Investigation

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“…It has also been shown that CaMKII can act to mediate troponin I function [8] and the promoter-region of the atrial myosin light chain-1 gene [25]. It now appears that CaMKII may be able to acutely induce a shift in the myofilament sensitivity to Ca 2+ to a more energetically favorable state after exercise training, although other studies have suggested that PKA mediates Ca 2+ sensitivity [26]. This is conceivable also in the current study, since CaMKIIblockade only partially blunted the training-induced increase in Ca 2+ sensitivity.…”

Section: Myofilament Ca 2+ Sensitivitymentioning

confidence: 99%

Aerobic interval training enhances cardiomyocyte contractility and Ca2+ cycling by phosphorylation of CaMKII and Thr-17 of phospholamban

Kemi

Ellingsen

Ceci

et al. 2007

Journal of Molecular and Cellular Cardiology

112

116

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Cardiac adaptation to aerobic exercise training includes improved cardiomyocyte contractility and calcium handling. Our objective was to determine whether cytosolic calcium/calmodulindependent kinase II and its downstream targets are modulated by exercise training. A six-week aerobic interval training program by treadmill running increased maximal oxygen uptake by 35% in adult mice, whereupon left ventricular cardiomyocyte function was studied and myocardial tissue samples were used for biochemical analysis. Cardiomyocytes from trained mice had enhanced contractility and faster relaxation rates, which coincided with larger amplitude and faster decay of the calcium transient, but not increased peak systolic calcium levels. These changes were associated with reduced phospholamban expression relative to sarcoplasmic reticulum calcium ATPase, and constitutively increased phosphorylation of phospholamban at the threonine 17, but not at the serine 16 site. Calcium-calmodulin-dependent kinase IIδ phosphorylation was increased at Threonine 287, indicating activation. To investigate the physiological role of calcium/ calmodulin-dependent kinase IIδ phosphorylation, this kinase was blocked specifically by autocamtide-2 related inhibitory peptide II. This maneuver completely abolished training-induced improvements of cardiomyocyte contractility and calcium handling, and blunted, but did not completely abolish the training-induced increase in Ca 2+ sensitivity. Also, inhibition of calcium/ calmodulin-dependent kinase II reduced the greater frequency-dependent acceleration of relaxation that was observed after aerobic interval training. These observations indicate that calcium/calmodulin-dependent kinase IIδ contributes significantly to the functional adaptation of the cardiomyocyte to regular exercise training.

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“…Since most of the abundant cytoplasmic proteins, i.e., the cytosolic and myofilamental proteins, as well as the most abundant nuclear proteins, i.e., the histones, are removed, the resulting nuclear protein extract appears to be aptly suited for further analysis of TF abundance and function. We are planning to apply this method to nuclear proteome profiling on remodeled [26] and hibernating [24] myocardium. Since there is minimal contamination of the nuclear protein extract with cytosolic proteins, this method is highly useful for the analysis of nuclear presence of TFs in different conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Cardiac tissue was collected from a total of 18 Yorkshire × Landrace swine. Animals were sedated by an intramuscular injection of a mixture of ketamine and midazolam, anesthetized with intravenous pentobarbital (bolus + continuous infusion), intubated, and ventilated [24,26]. The thorax and pericardium were opened and the heart was exposed.…”

Section: Experimental Animalsmentioning

confidence: 99%

“…In a subset of four pigs, dobutamine was infused in consecutive doses of 2.5 and 10 μg/kg/min, for 10 min each, followed by a 10-min wash out period. Heart rate and LV contractility were determined as previously described [24,26]. Then the heart was arrested by application of an electroshock from a 9-V battery [15] and immediately excised.…”

Section: Experimental Animalsmentioning

confidence: 99%

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Nuclear protein extraction from frozen porcine myocardium

et al. 2010

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Protocols for the extraction of nuclear proteins have been developed for cultured cells and fresh tissue, but sometimes only frozen tissue is available. We have optimized the homogenization procedure and subsequent fractionation protocol for the preparation of nuclear protein extracts from frozen porcine left ventricular (LV) tissue. This method gave a highly reproducible protein yield (6.5±0.7% of total protein; mean±SE, n=9) and a 6-fold enrichment of the nuclear marker protein B23. The nuclear protein extracts were essentially devoid of cytosolic, myofilament, and histone proteins. Compared to nuclear extracts from fresh LV tissue, some loss of nuclear proteins to the cytosolic fraction was observed. Using this method, we studied the distribution of tyrosinephosphorylated signal transducer and activator of transcription 3 (PY-STAT3) in LV tissue of animals treated with the β-agonist dobutamine. Upon treatment, PY-STAT3 increased 30.2±8.5-fold in total homogenates, but only 6.9±2.1-fold (n=4, P=0.03) in nuclear protein extracts. Of all PY-STAT3 formed, only a minor fraction appeared in the nuclear fraction. This simple and reproducible protocol yielded nuclear protein extracts that were highly enriched in nuclear proteins with almost complete removal of cytosolic and myofilament proteins. This nuclear protein extraction protocol is therefore well-suited for nuclear proteome analysis of frozen heart tissue collected in biobanks.

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Alterations in Myofilament Function Contribute to Left Ventricular Dysfunction in Pigs Early After Myocardial Infarction

Cited by 113 publications

References 66 publications

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

Aerobic interval training enhances cardiomyocyte contractility and Ca2+ cycling by phosphorylation of CaMKII and Thr-17 of phospholamban

Nuclear protein extraction from frozen porcine myocardium

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