Zinc homeostasis is vital to immune and other organ system functions, yet over a quarter of the world’s population is zinc deficient. Abnormal zinc transport or storage protein expression has been linked to diseases, such as cancer and chronic obstructive pulmonary disorder. Although recent studies indicate a role for zinc regulation in vascular functions and diseases, detailed knowledge of the mechanisms involved remains unknown. This study aimed to assess protein expression and localization of zinc transporters of the SLC39A/ZIP family (ZIPs) and metallothioneins (MTs) in human subcutaneous microvessels and to relate them to morphological features and expression of function-related molecules in the microvasculature. Microvessels in paraffin biopsies of subcutaneous adipose tissues from 14 patients undergoing hernia reconstruction surgery were analysed for 9 ZIPs and 3 MT proteins by MQCM (multifluorescence quantitative confocal microscopy). Zinc regulation proteins detected in human microvasculature included ZIP1, ZIP2, ZIP8, ZIP10, ZIP12, ZIP14 and MT1-3, which showed differential localization among endothelial and smooth muscle cells. ZIP1, ZIP2, ZIP12 and MT3 showed significantly (p < 0.05) increased immunoreactivities, in association with increased microvascular muscularization, and upregulated ET-1, α-SMA and the active form of p38 MAPK (Thr180/Tyr182 phosphorylated, p38 MAPK-P). These findings support roles of the zinc regulation system in microvascular physiology and diseases.
BackgroundThe increased adverse cardiac events in women undergoing coronary artery bypass grafting are multifactorial and may include clinical, psychosocial, and biological factors. Potential contributing biological factors could include vascular hyperreactivity of the internal mammary artery (IMA) to endogenous vasoconstrictors in women, resulting in a predilection to myocardial ischemia. This study evaluated sex differences in serotonin and thromboxane A2 dependent vasoconstriction in human isolated IMA, with the mechanistic role of (1) the endothelium, (2) nitric oxide (NO), (3) prostaglandins, and (4) receptor activity investigated for any observed sex difference.Methods and ResultsViable isolated human IMA segments were obtained from 116 patients (44 women [mean age, 66.8±12.2 years] and 72 men [mean age, 66.6±10.4 years]) undergoing coronary artery bypass grafting. Cumulative concentration‐response curves for serotonin and thromboxane A2 mimetic, U46619, were determined and revealed an increased sensitivity to serotonin but not U46619 in women. This sex difference to serotonin was further assessed by the following: (1) endothelial denudation, (2) endothelial NO synthase inhibition and NO quantification using electron paramagnetic resonance, (3) cyclooxygenase inhibition and prostaglandin metabolite quantification using mass spectrometry, and (4) quantification of receptor activity status. The female hyperreactivity to serotonin was (1) abolished by endothelial denudation; (2) unaffected by NO synthase inhibition, with no difference in electron paramagnetic resonance–assessed NO levels; (3) abolished by cyclooxygenase inhibition (quantification of prostaglandins in IMA revealed a trend towards reduced 6‐keto prostaglandin F1α in female IMA; P=0.08); and (4) unrelated to receptor activity.ConclusionsThese data indicate that female IMAs are hyperreactive to serotonin but not U46619, with the former attributable to an endothelium‐dependent cyclooxygenase pathway.
S8Heart, Lung and Circulation CSANZ 2012 Abstracts 2012;21:S1-S142 signalling may provide evidence for the development of cardiac-and/or gender-specific MR therapies. The aim of the current study was to (i) characterise the role of cardiomyocyte MR signalling in cardiac structural and functional remodelling, (ii) identify the signalling pathways regulated by cardiomyocyte MR and (iii) identify sex-specific regulation of those pathways using selective cardiomyocyte MR knockout mice (myo-MRKO). Hearts from wild-type (WT) and myo-MRKO were excised and subjected to 20 min global ischaemia using the Langendorff isolated mouse heart system (n = 4-9 per group, 16 weeks old). There were no differences in basal cardiac function between WT and myo-MRKO mice. Both male and female myo-MRKO hearts had greater cardiac function post ischaemia/reperfusion compared to WT. Recovery of left ventricular developed pressure (% basal) in male hearts was greater than females (male: WT 59.09 ± 8.86 mmHg, myo-MRKO 85.21 ± 6.09 mmHg, female: WT 40.55 ± 3.17 mmHg, myo-MRKO 66.38 ± 5.99 mmHg, p < 0.05). This sex response challenges conventional expectation that female hearts are protected from ischaemic injury. Preliminary data from male mice treated with DOC/salt for eight weeks show greater function at baseline compared to untreated mice (WT: untreated 88.41 ± 3.89 mmHg, DOC/salt 103.14 ± 2.44 mmHg, myo-MRKO: untreated 86.49 ± 4.26 mmHg, DOC/salt 96.47 ± 7.62 mmHg, p < 0.05) and no differences between treatment groups at end of reperfusion. These data demonstrate a key role for cardiomyocyte MR signalling in acute ischaemic injury. Ongoing studies are investigating cardiomyocyte MR signalling in ischaemia/reperfusion injury pathways in disease states. http://dx. We investigated whether macrophage migration inhibitory factor (MIF); a pro-inflammatory cytokine, promotes inflammation and exacerbates cardiac injury following myocardial infarction (MI).MIF knockout (MIFKO) and wild type (WT) mice were subjected to coronary artery occlusion. Within one week after MI, incidence of cardiac rupture was higher in WT than in MIFKO mice (69% vs. 29%, P = 0.002), which was associate with a higher density of CD45+ cells at day-3 (1213 cells/mm vs. 612 cells/mm) and upregulated expression of IL-1 and MCP-1 at 24 h post-MI. Further MMP-9 and -2 activities at day-3 and day-7 were also significantly higher in WT mice, respectively. To differentiate the role of MIF derived from cardiomyocytes or leukocytes, we generated chimeric mice via bone marrow transplantation (BMT), i.e. WT mice received BMT from MIFKO (WT KO ) and MIFKO mice received BMT from WT mice (KO WT ).Compared to WT KO counterparts, KO WT mice post-MI presented a higher incidence of cardiac rupture (40% vs. 10%), a greater CD45+ cell infiltration, reduced fractional shortening (16% vs. 25%) and enlarged ventricular diameter size measured by echocardiography. Moreover, histological analysis demonstrated a large fraction of the necrotic myocardium (30% vs. 18%), decreased collagen deposition (3...
Zinc homeostasis is vital to immune and other organ system functions, yet over a quarter of the world’s population are zinc deficient. Abnormal zinc transport or storage protein expression has been linked to diseases, such as cancer and chronic obstructive pulmonary disorder. Although recent studies indicate a role for zinc regulation in vascular functions and diseases, detailed knowledge of the mechanisms involved remain unknown. This study aimed to assess protein expression and localization of zinc transporters of the SLC39A/ZIP family (ZIPs) and metallothioneins (MTs) in human subcutaneous microvessels, and to relate them to morphologic features and expression of function-related molecules in the microvasculature. Microvessels in paraffin biopsies of subcutaneous adipose tissues from 14 patients undergoing hernia reconstruction surgery were analysed for 9 ZIPs and 3 MT proteins by MQCM (multifluorescence quantitative confocal microscopy). Zinc regulation proteins detected in human microvasculature included ZIP1, ZIP2, ZIP8, ZIP10, ZIP12, ZIP14, and MT1-3, which showed differential localization among endothelial and smooth muscle cells. ZIP1, ZIP2, ZIP12 and MT3 showed significantly (p < 0.05) increased immunoreactivities, in association with increased microvascular muscularization, and upregulated ET-1, α-SMA and the active form of p38 MAPK (Thr180/Tyr182 phosphorylated, p38 MAPK-P). These findings support roles of the zinc regulation system in microvascular physiology and diseases.
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