- Open Access
Deciphering the gene expression profile of peroxisome proliferator-activated receptor signaling pathway in the left atria of patients with mitral regurgitation
© Chen et al. 2016
Received: 8 December 2015
Accepted: 19 April 2016
Published: 2 June 2016
Differentially expressed genes in the left atria of mitral regurgitation (MR) pigs have been linked to peroxisome proliferator-activated receptor (PPAR) signaling pathway in the KEGG pathway. However, specific genes of the PPAR signaling pathway in the left atria of MR patients have never been explored.
This study enrolled 15 MR patients with heart failure, 7 patients with aortic valve disease and heart failure, and 6 normal controls. We used PCR assay (84 genes) for PPAR pathway and quantitative RT-PCR to study specific genes of the PPAR pathway in the left atria.
Gene expression profiling analysis through PCR assay identified 23 genes to be differentially expressed in the left atria of MR patients compared to normal controls. The expressions of APOA1, ACADM, FABP3, ETFDH, ECH1, CPT1B, CPT2, SLC27A6, ACAA2, SMARCD3, SORBS1, EHHADH, SLC27A1, PPARGC1B, PPARA and CPT1A were significantly up-regulated, whereas the expression of PLTP was significantly down-regulated in the MR patients compared to normal controls. The expressions of HMGCS2, ACADM, FABP3, MLYCD, ECH1, ACAA2, EHHADH, CPT1A and PLTP were significantly up-regulated in the MR patients compared to patients with aortic valve disease. Notably, only ACADM, FABP3, ECH1, ACAA2, EHHADH, CPT1A and PLTP of the PPAR pathway were significantly differentially expressed in the MR patients compared to patients with aortic valve disease and normal controls.
Differentially expressed genes of the PPAR pathway have been identified in the left atria of MR patients compared with patients with aortic valve disease and normal controls.
Mitral regurgitation (MR) is an important cause of heart failure secondary to valvular heart disease . Structural remodeling associated with atrial enlargement developed in the left atrial myocardium of MR patients with heart failure [2–4]. Differential gene expression related to the left atrial structural remodeling of MR has been reported in the pig MR model . Interestingly, gene ontology and pathway enrichment analysis of the differentially expressed genes in that study showed that peroxisome proliferator-activated receptor (PPAR) signaling pathway was identified in the KEGG pathway. However, specific genes of the PPAR signaling pathway that were differentially expressed in the left atrial myocardium of MR patients have never been explored.
The PPARs are ligand activated transcription factors that regulate genes important in cell differentiation, various metabolic processes, especially lipid and glucose homeostasis, insulin sensitivity, control of inflammatory processes and vascular integrity . The family of PPARs comprises three isoforms: PPARα, PPARβ/δ and PPARγ . PPARα is expressed mainly in metabolically active tissues, such as heart, liver, and skeletal muscle , and plays important physiologic roles in fatty acid oxidation and fatty acid metabolism.
In this study, we aim to explore the key element genes of the PPAR signaling pathway that were differentially expressed in the left atrial myocardium of MR patients vs. normal controls. The left atrial myocardium of patients with severe aortic valve disease was also used as a reference for gene analysis. The results from this study may identify specific genes of the PPAR signaling pathway that might be responsible for the atrial structural remodeling associated with atrial enlargement and progression of heart failure in patients with MR.
This study enrolled 15 severe non-ischemic MR patients with heart failure and sinus rhythm (age 57 ± 9 years) and 7 patients with severe degenerative aortic valve disease and heart failure in sinus rhythm (age 60 ± 11 years; aortic stenosis in 1, aortic regurgitation in 4, combined aortic stenoregurgitation in 2). Exclusion factors include previous myocardial infarction, febrile disorder, infectious or inflammatory disease, autoimmune disease, malignancy, acute or chronic viral hepatitis or use of immunosuppressive drugs. Informed consent was obtained from each study patient, and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee (102-2219C).
Atrial tissues of MR patients and aortic valve disease patients were sampled from the left atrial free wall during surgery. After excision, some atrial tissues were immediately frozen in liquid nitrogen. Additionally, some atrial tissues were placed into a Tissue Tek® container which was then filled with Tissue Tek® optimum cutting temperature compound (Sakura ® Finetek, CA, USA) and these samples were frozen in liquid nitrogen for later histochemical study.
PCR assay and data processing
RNAs were extracted from the myocardial tissue using a RiboPureTM kit (Ambion, Grand Island, NY, USA) according to the manufacturer’s protocol. RNA quality was assessed using an Agilent 2100 Bioanalyzer (Agilent Technologies Inc, Santa Clara, CA, USA). PPAR pathway related resources were obtained using information from website (https://www.qiagen.com/tw/shop/genes-and-pathways/pathway-details/?pwid=367). A total of 84 genes of the PPAR signaling pathway were examined by RT2 profiler PCR array (Qiagen, CA, USA) according to the manufacturer’s directions. Ribosomal protein, large, P0 (RPLP0) gene served as the endogenous control. Fold-change values greater than one indicated a positive- or an up-regulation, and fold-change values less than one indicated a negative or down-regulation.
Quantitative determination of RNAs by real-time RT-PCR
Primer sequences for real-time PCR
TGC GTT TTG GAA CCA AGC
CAT GCT GAT CTG TTA ATG ATA CCC
AGG AGC CAT TGA TGT GTG C
CTG CTT TGG TCT TTA TAC CAG CTA
CCT TGG GAA AAC AGC TAA ACC
CCA GAA CTC CTG GGT CAC A
ACA ACA AAA GCC CCT GAC TG
AGG GCA GAG AGA GCT ACA TCC
GCT GAA GGT TGG AGA AAT GC
CCT CAT GCC TGT GAG CTG
TGA CCG ACA CTT GTT TGC TC
GAG CTC AGG CAA GAT GAT CC
GTA CTG TGC CCA GGA TGC TT
CTC TGG TTC CCG ATG ACC T
CCT GGG CTG TCA CTA TAG GAT T
AGA AGC TGG GTT CCT CTT GC
CCC GGG ATA AGG ACA AGA G
CAT CTG CTT CTT CTG CAA ACC
CTG GGC ACC TGG AAG CTA
TGG TAG CAA AAC CCA CAC C
CCG CAA TGG ACC ATG TAA C
CAG CTC TAG CAT GGC CTT TT
GCG TCC CGT CTA AAG GTG T
ACC AGC TAA GAG TGG GAT CTT AAA
AGC CAA CCA TGC TCA ACT TC
CTC TTT TGG CCT TTC AGA AAT C
GAA CCA ATC TCA CCG ACA GG
GCC ACC CGA GTG TAA CCA TA
TGT TTC ATC AGT ATG CTT TGC AC
CAA ATT TGG GCA GTT GGA TT
TGC CGA GAG TGG AAC ACA C
AAA AGC AGC TGG ACC CTA CA
GGG CTT TTG GTT GTA CTG CT
AAA TTT CTT CTT TAA CAC ACA AGT GG
CTG CTC CTC ATG CTG GAC TA
GCC TGG ACA ATG GCT GAG
GAC GTC ATG ATG ATA AAG AGA TGA G
GAG GAA GCT CCT TTA GTG TCT GA
CTT CGG GGG AAC CTT CAA
GTG GTA GAG GAC AGG GCA GA
TTG CAC GTG GCA CTG ACT
GGA TGT TCC TTC ACG ATT GC
GGC ACC ATT GAA ATC CTG AG
GAA GGG GGA GAT GTT GAG C
Protein concentrations of atrial myocardial tissues were determined by the Bradford method (Bio-Rad) according to the supplier’s instructions. The HeLa cell lysate (Santa Cruz, Texas, USA) served as positive control. 20 μg protein extracts were electrophoresed on a 12 % acrylamide SDS-PAGE gel and immunoblotted onto PVDF membranes. The membranes were blocked for 1 h in PBST containing 5 % w/v nonfat dry milk. The primary antibodies, including anti-ACADM and ECH1 (Abcam, Cambridge, USA), were used to react with the blots at room temperature for 2 h. Immunoreactivity was revealed with horseradish peroxidase-conjugated secondary antibody. All specific values of proteins evaluated were standardized to GAPDH (GeneTex, CA, USA).
Oil red O staining
Left atrial tissues were sliced into 8-µm sections, stained with Oil red O to visualize lipid accumulation (ScyTek Laboratories, Utah, USA) according to the manufacturer’s directions. Sections were mounted and visualized using an Olympus BX51 microscope. The Oil red O stained area per myocyte was analyzed by Cellsens Dimension (Olympus, JAPAN) with at least 100 randomly chosen myocytes per each sample.
Data are presented as mean ± SD (baseline characteristics) or SEM (gene, proteins, and Oil red O staining expressions). Categorical variables were compared using Chi square test or Fisher exact test as appropriate. Continuous variables among 3 groups were analyzed by the Kruskal–Wallis Test, and continuous variables between 2 groups were analyzed by the Mann–Whitney Test. Statistical analysis was performed using commercial statistical software (IBM SPSS Statistics 22). A P value of <0.05 was considered statistically significant.
Baseline characteristics of patients studied
Baseline clinical characteristics of the study patients
MR (n = 15)
AVD (n = 7)
NC (n = 3)
57 ± 9
60 ± 11
6 (40.0 %)
6 (85.7 %)
2 (13.3 %)
1 (14.3 %)
Body mass index (kg/m2)
23.5 ± 2.3
24.2 ± 3.3
7 (46.7 %)
4 (57.1 %)
Diabetes mellitus (%)
2 (13.3 %)
1 (14.3 %)
6 (40.0 %)
2 (28.6 %)
Functional class I (%)
2 (13.3 %)
1 (14.3 %)
Functional class II (%)
7 (46.7 %)
3 (42.9 %)
Functional class III (%)
6 (40.0 %)
2 (28.6 %)
Functional class IV (%)
0 (0.0 %)
1 (14.3 %)
Aortic valve disease (%)
0 (0.0 %)
7 (100.0 %)
Tricuspid regurgitation (%)
7 (46.7 %)
1 (14.3 %)
5 (33.3 %)
0 (0.0 %)
Calcium channel blockers (%)
6 (40.0 %)
3 (42.9 %)
Angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (%)
12 (80.0 %)
3 (42.9 %)
0.9 ± 0.7
1.0 ± 0.3
White blood cell count (103/uL)
6.3 ± 1.5
5.6 ± 1.8
Left atrial diameter (mm)
45.5 ± 6.0
38.9 ± 5.8
Left atrial maximal volume (mL)
87.3 ± 42.6
42.5 ± 25.6
Left atrial ejection fraction (%)
49.7 ± 11.9
45.6 ± 18.7
Left ventricular end-diastolic diameter (mm)
58.2 ± 7.3
59.9 ± 12.7
Left ventricular ejection fraction (%)
67.3 ± 11.5
61.6 ± 12.9
The left atrial size was significantly larger in the MR patients with heart failure than patients with aortic valve disease and heart failure (P < 0.05). The MR patients with heart failure and patients with aortic valve disease and heart failure did not significantly differ in left ventricular size and ejection fraction.
Gene expression profiling analysis of the PPAR signaling pathway through PCR assay in the left atrium of MR patients with heart failure vs. normal controls
Selected signature mRNA expression of the PPAR signaling pathway through PCR assay in the left atria of mitral regurgitation patients with heart failure vs. normal control
3-hydroxy-3-methylglutaryl-CoA synthase 2
Acyl-CoA dehydrogenase, C-4 to C-12 straight chain
Fatty acid binding protein 3, muscle and heart (mammary-derived growth inhibitor)
Enoyl CoA hydratase 1, peroxisomal
Carnitine palmitoyltransferase 1B
Carnitine palmitoyltransferase 2
Solute carrier family 27 (fatty acid transporter), member 6
Acetyl-CoA acyltransferase 2
Enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase
Solute carrier family 27 (fatty acid transporter), member 1
Acyl-CoA synthetase long-chain family member 3
Carnitine palmitoyltransferase 1A
Phospholipid transfer protein
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 3
Peroxisome proliferator-activated receptor gamma, coactivator 1 beta
Signaling and stimulation of insulin
Sorbin and SH3 domain containing 1
Peroxisome proliferator-activated receptor alpha
Kruppel-like factor 10
Mediating protein–protein interactions
Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog
Matrix metallopeptidase 9
Quantitative PCR validation of differentially expressed mRNAs of the PPAR signaling pathway in the left atria among MR patients with heart failure, patients with aortic valve disease and heart failure, and normal controls
The left atrial myocardium of patients with severe aortic valve disease and heart failure was also used as a reference for gene analysis of the PPAR signaling pathway.
The expressions of APOA1 (4.65 ± 0.52 vs. 7.37 ± 0.81, P = 0.011), ACADM (1.40 ± 0.09 vs. 3.38 ± 0.46, P = 0.001), FABP3 (−2.83 ± 0.19 vs. −1.58 ± 0.32, P = 0.006), ETFDH (2.41 ± 0.13 vs. 4.29 ± 0.21, P = 0.001), ECH1 (0.25 ± 0.10 vs. 2.18 ± 0.17, P = 0.001), CPT1B (3.65 ± 0.18 vs. 6.06 ± 0.22, P = 0.001), CPT2 (3.75 ± 0.16 vs. 6.22 ± 0.29, P = 0.001), SLC27A6 (3.29 ± 0.19 vs. 5.76 ± 0.71, P = 0.005), ACAA2 (2.63 ± 0.11 vs. 4.25 ± 0.34, P = 0.001), SMARCD3 (2.93 ± 0.11 vs. 4.33 ± 0.33, P = 0.002), SORBS1 (6.08 ± 0.16 vs. 7.71 ± 0.66, P = 0.005), EHHADH (4.65 ± 0.19 vs. 5.92 ± 0.43, P = 0.017), SLC27A1 (3.83 ± 0.16 vs. 5.94 ± 0.37, P = 0.001), PPARGC1B (4.61 ± 0.23 vs. 8.10 ± 0.71, P = 0.001), PPARA (4.84 ± 0.17 vs. 6.80 ± 0.37, P = 0.001) and CPT1A (5.60 ± 0.17 vs. 6.82 ± 0.33, P = 0.005) in the left atria were significantly up-regulated in the MR patients with heart failure (n = 14) compared to normal controls (n = 6; 24-year-old Caucasian male, 27-year-old Caucasian male, 30-year-old Asian male, 60-year-old Caucasian female, 76-year-old Caucasian female and 77-year-old Caucasian male, purchased from BioChain, Newark, CA, USA). Whereas the expression of PLTP (4.22 ± 0.14 vs. 2.77 ± 0.48, P = 0.006) in the left atria was significantly down-regulated in the MR patients with heart failure compared to normal controls.
The expressions of ETFDH (3.12 ± 0.36 vs. 4.29 ± 0.21, P = 0.037), ECH1 (1.10 ± 0.24 vs. 2.18 ± 0.17, P = 0.010), CPT1B (3.76 ± 0.31 vs. 6.06 ± 0.22, P = 0.004), CPT2 (3.81 ± 0.19 vs. 6.22 ± 0.29, P = 0.004), SMARCD3 (2.84 ± 0.14 vs. 4.33 ± 0.33, P = 0.006), SORBS1 (6.08 ± 0.33 vs. 7.71 ± 0.66, P = 0.037), SLC27A1 (3.57 ± 0.27 vs. 5.94 ± 0.37, P = 0.004), PPARGC1B (4.34 ± 0.24 vs. 8.10 ± 0.71, P = 0.004) and PPARA (5.10 ± 0.31 vs. 6.80 ± 0.37, P = 0.010) in the left atria were significantly up-regulated in the patients with aortic valve disease and heart failure (n = 7) compared to normal controls (n = 6). Whereas the expression of PLTP (5.08 ± 0.15 vs. 2.77 ± 0.48, P = 0.006) in the left atria was significantly down-regulated in the patients with aortic valve disease and heart failure compared to normal controls.
The expressions of HMGCS2 (10.18 ± 0.52 vs. 12.35 ± 0.23, P = 0.011), ACADM (1.40 ± 0.09 vs. 2.18 ± 0.36, P = 0.039), FABP3 (−2.83 ± 0.19 vs. −1.92 ± 0.24, P = 0.011), MLYCD (11.96 ± 0.20 vs. 13.03 ± 0.20, P = 0.006), ECH1 (0.25 ± 0.10 vs. 1.10 ± 0.24, P = 0.008), ACAA2 (2.63 ± 0.11 vs. 3.64 ± 0.22, P = 0.002), EHHADH (4.65 ± 0.19 vs. 5.49 ± 0.22, P = 0.014), CPT1A (5.60 ± 0.17 vs. 6.28 ± 0.13, P = 0.017) and PLTP (4.22 ± 0.14 vs. 5.08 ± 0.15, P = 0.004) in the left atria were significantly up-regulated in the MR patients with heart failure compared to patients with aortic valve disease and heart failure.
The expression of fatty acid oxidation enzymes (ACADM, ECH1) in the left atria among MR patients with heart failure, patients with aortic valve disease and heart failure, and normal controls
The expression of ACADM protein (1.81 ± 0.11 vs. 1.43 ± 0.09, P = 0.011) in the left atria was significantly up-regulated in the patients with aortic valve disease and heart failure (n = 6) compared to normal controls (n = 4) (Fig. 2). The expression of ECH1 protein (2.07 ± 0.30 vs. 1.70 ± 0.27, P = 0.670) in the left atria was up-regulated in the patients with aortic valve disease and heart failure (n = 6) compared to normal controls (n = 4), although the difference did not reach statistical significance.
The expressions of ACADM (2.49 ± 0.34 vs. 1.81 ± 0.11, P = 0.065) and ECH1 (2.84 ± 0.30 vs. 2.07 ± 0.30, P = 0.129) proteins in the left atria were up-regulated in the MR patients with heart failure (n = 10) compared to patients with aortic valve disease and heart failure (n = 6), although the difference did not reach statistical significance (Fig. 2).
Left atrial myocytes fat staining
This study identifies and reports the altered gene expression pattern of the PPAR signaling pathway in the left atria among MR patients with heart failure, patients with aortic valve disease and heart failure, and normal controls without valve disease and heart failure. Notably, seven genes (ACADM, FABP3, ECH1, ACAA2, EHHADH, CPT1A and PLTP) of the PPAR signaling pathway were differentially expressed in the left atria of MR patients compared to patients with aortic valve disease and normal controls.
The PPAR transcriptional regulatory complex controls the expression of fatty acid utilization genes by binding to specific promoter DNA response elements with its heterodimeric partner, the retinoid X receptor, and interacting with PPARγ coactivator-1α to recruit other cofactors with histone acetylase activity to initiate gene transcription for fatty acid oxidation . The myocardium utilizes primarily fatty acids for ATP production via mitochondrial fatty acid oxidation. However, altered expression of the fatty acid oxidation enzymes can impair mitochondrial metabolism and lead to pathologic remodeling of myocardium, probably through lipotoxicity, reactive oxidative stress overproduction, and ATP deficiency [9–11]. Our prior studies showed that altered mitochondrial function and reactive oxidative stress overproduction due to nox2 containing NADPH oxidase activity developed in the atria of MR patients with heart failure [12, 13]. Moreover, heart-specific overexpression of PPAR induced several target genes involved in fatty acid utilization and increased cardiac fatty acid uptake and oxidation . In contrast, heart-specific overexpression of PPAR markedly diminished the expression of genes involved in glucose metabolism leading to impaired glucose uptake and utilization . Of note, our prior study showed that glycogen accumulation increased in the atrial myocytes of MR patients . Moreover, this study showed that lipid accumulation in the atrial myocytes was significantly increased in the MR patients with heart failure compared to normal controls.
Acyl-CoA dehydrogenase, C-4 to C-12 straight chain (ACADM) gene provides instructions for making an enzyme called medium-chain acyl-CoA dehydrogenase, which functions within mitochondria and is essential for fatty acid oxidation to metabolize medium-chain fatty acids .
Fatty-acid-binding protein 3, muscle and heart (FABP3), also known as heart-type FABP, is an intracellular lipid-binding protein for transporting fatty acids and other lipophilic substances from the cytoplasm to the nucleus and subsequently, PPAR activation by fatty acid ligands [8, 15]. Glatz JF et al.  reported that FABP overexpression in skeletal muscle increased fatty acids transported into the muscle cell and consequently, fatty acid oxidation was increased. On the other hand, PPAR can regulate the expression of FABP3 .
Enoyl-CoA hydratase1 (ECH1), a mitochondrial β-oxidation enzyme, has been shown to play an important role for mitochondrial integrity and function . The expression of ECH1 in tissue is associated with nitric oxide availability  and a decreased production of nitric oxide by the mitochondrial form of nitric oxide synthase has been proposed as a cause of decreased mitochondrial biogenesis, resulting in impairment of cellular turnover, tissue regeneration and lipid metabolism .
Acetyl-CoA acyltransferase 2 (ACAA2) encoding protein catalyzes the last step of the mitochondrial fatty acid β-oxidation spiral. Additionally, ACAA2 has been demonstrated to have antiapoptotic effects, which provided a possible linkage between fatty acid metabolism and apoptosis of cells .
Enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase (EHHADH), regulated and mediated by PPARα, encodes a protein that is an l-bifunctional enzyme essential for the peroxisomal β-oxidation pathway to the breakdown of very long chain fatty acids and is indispensable for the production of medium-chain dicarboxylic acids .
Carnitine palmitoyltransferase 1 (CPT1) is one of the carnitine cycle enzymes that plays a role in the transportation of long-fatty acids into the mitochondria for ß-oxidation that allows the body to process fats to provide energy during times of fasting and illness .
Phospholipid transfer protein (PLTP) is a widely expressed lipid transfer protein participating in lipoprotein metabolism in the plasma and tissues . PLTP activity is a risk factor for coronary artery disease  and PLTP also plays a role in inflammation and oxidative stress .
Taken together, this study demonstrated that the altered expression of ACADM, FABP3, ECH1, ACAA2, EHHADH, CPT1A and PLTP of the PPAR signaling pathway in the left atria of MR patients compared to patients with aortic valve disease and normal controls should play a substantially role in the altered fatty acid metabolism (Fig. 3), glucose metabolism, energy utilization, and pathologic remodeling (hypertrophy, myolysis, glycogen accumulation, apoptosis, autophagy and inflammation) in the atria of MR patients, either partly through altered mitochondrial function, reactive oxidative stress overproduction, inflammation and apoptosis or partly as an adaptive response to volume overload of MR [3, 4, 12, 13, 26].
There are several limitations in this study. Firstly, the number of study subjects was relatively small. However, the quantitative real-time RT-PCR results were significant and consistent with PCR assay. Secondly, the functional roles of ACADM, FABP3, ECH1, ACAA2, EHHADH, CPT1A and PLTP of the PPAR signaling pathway on the regulation of atrial structural remodeling of MR patients were not specifically examined in this study.
Differentially expressed genes of the PPAR signaling pathway have been identified in the left atria of MR patients compared to patients with aortic valve disease and normal controls. Moreover, lipid accumulation in the atrial myocytes was significantly increased in the MR patients compared to normal controls. As the PPAR transcriptional regulatory complex controls the expression of fatty acid utilization genes in the myocardium, the results of this study provide rationale for metabolic therapy to remedy atrial structural remodeling associated with atrial enlargement and progression of heart failure in patients with MR.
MCC designed the study, analysed data and wrote the paper. JPC and WCH performed experiments, analysed data and contributed to the paper. WHL and THC analysed data and contributed to the paper. YSL, KLP, YKH, CYF and CJC recruited patients, analysed data and contributed to the paper. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
This work was supported by grants from the National Science Council, Taiwan (Grants NSC 102-2314-B-182A-107-MY2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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