Korean J Physiol Pharmacol.  2017 May;21(3):353-360. 10.4196/kjpp.2017.21.3.353.

Expression profile of mitochondrial voltage-dependent anion channel-1 (VDAC1) influenced genes is associated with pulmonary hypertension

• Zhou T
• Tang H
• Han Y
• Fraidenburg D
• Kim YW
• Lee D
• Choi J
• Bang H
• Ko JH

• KMID: 2376964
• DOI: http://doi.org/10.4196/kjpp.2017.21.3.353

Abstract

Several human diseases have been associated with mitochondrial voltage-dependent anion channel-1 (VDAC1) due to its role in calcium ion transportation and apoptosis. Recent studies suggest that VDAC1 may interact with endothelium-dependent nitric oxide synthase (eNOS). Decreased VDAC1 expression may limit the physical interaction between VDAC1 and eNOS and thus impair nitric oxide production, leading to cardiovascular diseases, including pulmonary arterial hypertension (PAH). In this report, we conducted meta-analysis of genome-wide expression data to identify VDAC1 influenced genes implicated in PAH pathobiology. First, we identified the genes differentially expressed between wild-type and Vdac1 knockout mouse embryonic fibroblasts in hypoxic conditions. These genes were deemed to be influenced by VDAC1 deficiency. Gene ontology analysis indicates that the VDAC1 influenced genes are significantly associated with PAH pathobiology. Second, a molecular signature derived from the VDAC1 influenced genes was developed. We suggest that, VDAC1 has a protective role in PAH and the gene expression signature of VDAC1 influenced genes can be used to i) predict severity of pulmonary hypertension secondary to pulmonary diseases, ii) differentiate idiopathic pulmonary artery hypertension (IPAH) patients from controls, and iii) differentiate IPAH from connective tissue disease associated PAH.

Keyword

Gene expression; Hypoxia; Molecular signature; Pulmonary hypertension; VDAC1

MeSH Terms

Animals
Anoxia
Apoptosis
Calcium
Cardiovascular Diseases
Connective Tissue Diseases
Fibroblasts
Gene Expression
Gene Ontology
Humans
Hypertension
Hypertension, Pulmonary*
Ion Transport
Lung Diseases
Mice
Mice, Knockout
Nitric Oxide
Nitric Oxide Synthase
Pulmonary Artery
Transcriptome
Calcium
Nitric Oxide
Nitric Oxide Synthase

Figure

• 

  Fig. 1 The VIP signature.(A) Gene ontology analysis on the 11 genes of the VIP signature. The top 20 GO terms associated with the VIP genes are listed. The p-values were calculated by Fisher's exact test. The vertical dash line denotes the significance level of 0.05. (B) Principal component analysis on the VIP gene expression in the discovery cohort. PC1, the first principal component; PC2, the second principal component. (C) Comparison of the VIP based S1 between controls and patients with secondary PH. (D) Comparison of the VIP based S2 between controls and patients with IPAH. (E) Comparison of the VIP based S3 between patients with secondary PH and patients with IPAH. The violin plots in panel C, D, and E indicate the distribution of S1, S2, and S3, respectively. CTRL, healthy controls; IPF-PH, patients with secondary PH induced by IPF.

• 

  Fig. 2 The VIP based S1 predicts severity of secondary PH in the Toronto cohort.(A) Positive correlation between S1 and PH severity. Non-PH, patients without PH; In-PH, patients with intermediate PH; Se-PH, patients with severe PH. (B) Superior predictive power of the VIP based S1 compared with random gene signature. The grey area shows the distribution of correlation coefficient (ρ) for 1,000 resampled gene signatures picked up from human genome with identical size as VIP. The black triangle stands for the ρ value of VIP. Right-tailed p-value of the sampling distribution was calculated.

• 

  Fig. 3 The VIP based S2 differentiates IPAH from controls in the Pittsburgh cohort.(A) Violin plots of S2 for both controls and patients with IPAH. The p-value was computed by t-test. CTRL: controls. (B) The ROC curve of the VIP signature in distinguishing IPAH patients from controls. (C) Superior classification power of the VIP based S2 compared with random gene signature. The grey area shows the distribution of AUC for 1,000 resampled gene signatures. The black triangle stands for the AUC of VIP. Right-tailed p-value of the sampling distribution was calculated.

• 

  Fig. 4 The VIP based S3 differentiates IPAH from SSc-PAH in the Pittsburgh cohort.(A) Violin plots of S3 for both SSc-PAH and IPAH patients. The p-value was computed by t-test. (B) The ROC curve of the VIP signature in distinguishing IPAH patients from SSc-PAH patients. (C) Superior classification power of the VIP based S3 compared with random gene signature. The grey area shows the distribution of AUC for 1,000 resampled gene signatures. The black triangle stands for the AUC of VIP. Right-tailed p-value of the sampling distribution was calculated.

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