Expression of BNP and BNP mRNA is augmented in the atria with increased pressure, and distributed predominantly in the subendocardial side. The level of BNP mRNA was well correlated with that of ANP mRNA. Thus, these two genes might be commonly regulated in response to atrial pressure.
Aortic aneurysm is a complex multifactorial disease with genetic and environmental risk factors. It is often accompanied by aortic calcification. Here, to uncover proteins that are significantly changed in calcified abdominal aortic aneurysms (CAAs) and calcified thoracic aortic aneurysms (CTAs) compared with those in adjacent normal aorta tissues, comprehensive analysis of differentially expressed proteins in their tissues was performed by a quantitative proteomic approach with iTRAQ labeling in combination with nanoLC-MALDI-TOF/TOF-MS/MS followed by ProteinPilot analysis. The proteomic analysis revealed 138 and 134 proteins differentially expressed in CAAs and CTAs in contrast to neighboring normal aorta tissues with high confidence, respectively. Significantly increased expression (≥1.3-fold) was found in 41 and 28 proteins, whereas decreased expression (<0.77-fold) was found in 4 and 60 proteins in CAAs and CTAs, respectively. Among them, we identified already known proteins involved in aneurysm formation and vascular calcification, such as type I and III collagen, matrix Gla protein, and α-2-HS-glycoprotein in CAAs and fibrinogen α, β and γ chains and α-2-HS-glycoprotein in CTAs with increased expression and mimecan in CAAs and fibulin-5 in CTAs with decreased expression. Based on the Panther pathway and Genesis clustering analyses, some of the proteins could be linked to corresponding biochemical pathways, such as the integrin signaling pathway with increased expression in CAAs, the blood coagulation pathway with increased expression in CTAs, and the inflammation mediated by chemokine and cytokine signaling pathway and the glycolysis pathway with decreased expression in CTAs. Interestingly, it was found by clustering analysis that samples from CAAs of patients with both CAAs and CTAs were clustered outside the samples of patients with CAAs and were clustered with samples of patients with CTAs. Our results provide a comprehensive patient-based proteomic analysis for the identification of potential biomarkers for CAAs and CTAs.
Calcification of aortic valves results in valvular aortic stenosis and is becoming a common valvular condition in elderly populations. An understanding of the molecular mechanisms of this valve lesion is important for revealing potential biomarkers associated with the development and progression of this disease. In order to identify proteins that are differentially expressed in calcific aortic valves (CAVs) compared with those in adjacent normal valvular tissues, comprehensive analysis of differentially expressed proteins in the tissues was done by a quantitative proteomic approach with isobaric tag for absolute and relative quantitation labeling followed by nanoliquid chromatography matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry. The proteomic analysis revealed 105 proteins differentially expressed in CAVs in contrast to adjacent normal valvular tissues with high confidence. Significantly increased expression (≥1.3-fold) was found in 34 proteins, whereas decreased expression (<0.77-fold) was found in 39 proteins in CAVs. Among them, α-2-HS-glycoprotein showed the greatest increase in expression (6.54-fold) and tenascin-X showed the greatest decrease in expression (0.37-fold). Numerous extracellular matrix proteins such as collagens were identified as proteins with significantly decreased expression. Panther pathway analysis showed that some of the identified proteins were linked to blood coagulation and integrin signaling pathways. Cluster analysis of the 105 proteins differentially expressed in CAVs based on the expression pattern revealed that tenascin-X was clustered with proteins controlling collagen structure and function, especially collagen fibrillogenesis, such as decorin and fibromodulin. We confirmed decreased levels of these proteins in CAVs by Western blot analyses. These results indicated that massive destruction of the extracellular matrix occurs in CAVs.
Deep hypothermic circulatory arrest (DHCA) is a protective method against brain ischemia in aortic surgery. However, the possible effects of DHCA on the plasma proteins remain to be determined. In the present study, we used novel high-throughput technology to compare the plasma proteomes during DHCA (22°C) with selective cerebral perfusion (SCP, n=7) to those during normothermic cardiopulmonary bypass (CPB, n=7). Three plasma samples per patient were obtained during CPB: T1, prior to cooling; T2, during hypothermia; T3, after rewarming for the DHCA group and three corresponding points for the normothermic group. A proteomic analysis was performed using isobaric tag for relative and absolute quantification (iTRAQ) labeling tandem mass spectrometry to assess quantitative protein changes. In total, the analysis identified 262 proteins. The bioinformatics analysis revealed a significant upregulation of complement activation at T2 in normothermic CPB, which was suppressed in DHCA. These findings were confirmed by the changes of the terminal complement complex (SC5b-9) levels. At T3, however, the level of SC5b-9 showed a greater increase in DHCA compared to normothermic CPB, while 48 proteins were significantly downregulated in DHCA. The results demonstrated that DHCA and rewarming potentially exert a significant effect on the plasma proteome in patients undergoing aortic surgery.
BackgroundAortic aneurysm is an increasingly common vascular disorder with fatal implication. However, there is no established diagnosis other than that based on aneurysmal size. For this purpose, serum protein biomarkers for aortic aneurysms are valuable. Although most of the studies on serum biomarker discovery have been based on comparison of serum proteins from the patient group with those from the healthy group, we considered that comparison of serial protein profiles such as those in presurgical and postsurgical sera within one patient would facilitate identification of biomarkers since the variability of serial protein profiles within one patient is smaller than that between groups. In this study, we examined serum proteins with differential levels in postsurgery compared with those in presurgery after the removal of aneurysmal tissues in abdominal aortic aneurysm (AAA) and thoracic aortic aneurysm (TAA) patients in order to identify potential serum biomarkers for AAAs and TAAs.ResultsA proteomic approach with an isobaric tag for relative and absolute quantitation (iTRAQ) labeling followed by nano liquid chromatography (nanoLC)-matrix-assisted laser desorption ionization (MALDI)-time of flight (TOF/TOF)-tandem mass spectrometry (MS/MS) was used. In the sera of patients with AAAs and TAAs, a total of 63 and 71 proteins with differential levels were further narrowed down to 6 and 8 increased proteins (≧1.3 fold, postsurgical vs. presurgical) (p < 0.05, patient vs. control) and 12 and 17 decreased proteins (< 0.77 fold, postsurgical vs. presurgical) (p < 0.05, patient vs. control) in postsurgical sera compared with those in presurgical sera, respectively. All of the increased proteins in postsurgical sera of both AAA and TAA patients included several known acute-phase proteins. On the other hand, in the decreased proteins, we found intriguing molecules such as α-2-macroglobulin, gelsolin, kallistatin, and so on. Among them, we confirmed that kallistatin in both AAA and TAA patients and α-2-macroglobulin in TAA patients showed decrease levels in postsurgical sera similar to those in control sera by Western blot analysis with other sera from AAA and TAA patients.ConclusionsTaken together, our findings suggest that Kallistatin and α-2-macroglobulin are potential serum biomarkers for both AAA and TAA and TAA, respectively.
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