In many fishes, upper thermal tolerance is thought to be limited in part by the heart's ability to meet increased oxygen demands during periods of high temperature. Temperature-dependent plasticity within the cardiovascular system may help fishes cope with the thermal stress imposed by increasing water temperatures. In this study, we examined plasticity in heart morphology and function in juvenile Atlantic salmon (Salmo salar) reared under control (+0°C) or elevated (+4°C) temperatures. Using noninvasive Doppler echocardiography, we measured the effect of acute warming on maximum heart rate, stroke distance, and derived cardiac output. A 4°C increase in average developmental temperature resulted in a>5°C increase in the Arrhenius breakpoint temperature for maximum heart rate and enabled the hearts of these fish to continue beating rhythmically to temperatures approximately 2°C higher than control fish. However, these differences in thermal performance were not associated with plasticity in maximum cardiovascular capacity, as peak measures of heart rate, stroke distance, and derived cardiac output did not differ between temperature treatments. Histological analysis of the heart revealed that while ventricular roundness and relative ventricle size did not differ between treatments, the proportion of compact myocardium in the ventricular wall was significantly greater in fish raised at elevated temperatures. Our findings contribute to the growing understanding of how the thermal environment can affect phenotypes later in life and identifies a morphological strategy that may help fishes cope with acute thermal stress.
The membrane bound matrix metalloproteinase MT1-MMP plays roles in modulating cell movement, independent of its abilities to remodel the extracellular matrix. Unlike many MMPs, MT1-MMP is activated in the Golgi prior to secretion by a pro-protein convertase, primarily furin. Regulation of the activation of pro-MT1-MMP has been methodically investigated, as altering the level of the active protein has broad implications in both activating other pro-MMPs, including pro-MMP-2, and many subsequent remodelling events. Our previous work in MCF-7 cells has demonstrated that modest, and not extremely high, levels of active MT1-MMP manifests into altered cell morphology and movement. At this low but optimal amount of MT1-MMP protein, changes to MT1-MMP levels are always mirrored by MMP-9 and pERK levels, and always opposite to MMP-2 levels. In this study, stable expression of the furin inhibitor α1-antitrypsin Portland (α1-PDX) in MDA-MB-231 cells increased overall MT1-MMP levels, but cells maintained a 21% proportion of pro-MT1-MMP. The increase in MT1-MMP was mirrored by increases in MMP-9 and pERK, but a decrease in MMP-2. These changes were associated with increased NF-κB transcription. In vitro analysis showed that α1-PDX decreased cell protrusions and migration, and this manifested as decreased tumourigenesis when examined in vivo using a chick CAM assay.
Measures of cardiac performance are pertinent to the study of thermal physiology and exercise in teleosts, particularly as they pertain to migration success. Increased heart rate, stroke volume and cardiac output have previously been linked to improved swimming performance and increased upper thermal tolerance in anadromous salmonids. To assess thermal performance in fishes, it has become commonplace to measure the response of maximum heart rate to warming using electrocardiograms. However, electrocardiograms do not provide insight into the hemodynamic characteristics of heart function that can impact whole-animal performance. Doppler echocardiography is a popular tool used to examine live animal processes, including real-time cardiac function. This method allows for nonsurgical measurements of blood flow velocity through the heart and has been used to detect abnormalities in cardiovascular function, particularly in mammals. Here, we show how a mouse Doppler echocardiograph system can be adapted for use in a juvenile salmonid over a range of temperatures and timeframes. Using this compact, noninvasive system, we measured maximum heart rate, atrioventricular (AV) blood flow velocity, the early flow-atrial flow ratio and stroke distance in juvenile Atlantic salmon (Salmo salar) during acute warming. Using histologically determined measures of AV valve area, we show how stroke distance measurements obtained with this system can be used to calculate ventricular inflow volume and approximate cardiac output. Further, we show how this Doppler system can be used to determine cardiorespiratory thresholds for thermal performance, which are increasingly being used to predict the consequences that warming water temperatures will have on migratory fishes.
BackgroundMT1-MMP is a cell-surface enzyme whose regulation of pro-MMP-2 and ERK activation position it as a key facilitator of ECM remodelling and cell migration. These processes are modulated by endogenous MMP inhibitors, such as RECK, a GPI-anchored protein which has been shown to inhibit both MT1-MMP and MMP-2 activity. Our previous studies have revealed a link between MT1-MMP levels, and pro-MMP-2 and ERK activation in mammalian cells, as well as MT1-MMP and RECK co-localization in Xenopus embryos. We here investigated how modulation of RECK would impact MT1-MMP and MMP-2 levels, as well as ERK signalling in Xenopus A6 cells.ResultsWe used a Morpholino approach to knockdown RECK, plasmid transfection to overexpress RECK, and PI-PLC treatment to shed RECK from the cell surface of Xenopus A6 cells. RECK reduction did not alter pERK or MT1-MMP levels, nor MMP-2 activity as measured by zymography; thus RECK-knockdown cells maintained the ability to remodel the ECM. RECK overexpression and PI-PLC treatment both increased ECM remodelling potential through increased MT1-MMP protein and relative MMP-2 activation levels.ConclusionsRECK changes that reduce the ability of the cell to remodel the ECM (overexpression and cell surface shedding) are compensated for by increases in MT1-MMP, and MMP-2 levels as seen by zymography.
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