Relationship Between Myocardial Injury and Expression of PGC-1α and Its Coactivators in Chronic Keshan Disease

Abstract

Objective

Keshan disease (KD) is a mitochondrial cardiomyopathy. The present study explored the roles of peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), the key regulator of mitochondrial structure and function, and its coactivators in myocardial injury in chronic KD. Furthermore, the usefulness of these molecules in the diagnosis of chronic KD was assessed.

Methods

In the present case-control study, 43 patients with chronic KD and 30 healthy individuals living in KD endemic areas were included. The myocardial injury indicators and mRNA expression levels of PGC-1α, nuclear respiratory factor 1 (NRF1), PPARα, and estrogen-related receptor alpha (ERRα) in peripheral blood were examined.

Results

It was found that the levels of atrial natriuretic peptide, creatine kinase, and lactate dehydrogenase (LDH) were higher in patients with chronic KD, when compared to controls, while the level of bradykinin was lower. Furthermore, the PGC-1α, NRF1 and PPARα mRNA levels were higher in patients with KD. The area under the receiver operating characteristic curve and the optimal diagnostic threshold of LDH was 0.937 and 304.0 U/L, respectively. It is noteworthy that the area under the combined receiver operating characteristic curve was larger, when compared to that for LDH detection alone (Z=2.055, P=0.0399). The area under the curve for the “LDH+PPARα” combination was 0.984, with 96.7% sensitivity and 93.0% specificity.

Conclusion

The combined detection of LDH and the expression of PPARα can be performed to diagnose the chronic KD.

Keywords

Keshan disease / peroxisome proliferator-activated receptor-γ coactivator-1α / myocardial injury / lactate dehydrogenase

References

[1] LoscalzoJ. Keshan disease, selenium deficiency, and the selenoproteome. N Engl J Med, 2014, 370(18): 1756-1760

[2] YangFY, LinZH, LiSG, et al.. Keshan disease—an endemic mitochondrial cardiomyopathy in China. J Trace Elem Electrolytes Health Dis, 1988, 2(3): 157-163

[3] FinckBN, KellyDP. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) regulatory cascade in cardiac physiology and disease. Circulation, 2007, 115(19): 2540-2548

[4] LarssonNG, WangJM, WilhelmssonH, et al.. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet, 1998, 18(3): 231-236

[5] VegaRB, HussJM, KellyDP. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol, 2000, 20(5): 1868-1876

[6] HussJM, TorraIP, StaelsB, et al.. Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol Cell Biol, 2004, 24(20): 9079-9091

[7] The Ministry of Health of the People’s Republic of ChinaDiagnosis of Keshan disease (WS/T 210-2011), 2011, Beijing, Standards Press of China(Chinese)

[8] DuanSZ, IvashchenkoCY, RussellMW, et al.. Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-gamma both induce cardiac hypertrophy in mice. Circ Res, 2005, 97(4): 372-379

[9] SchuppM, KintscherU, FielitzJ, et al.. Cardiac PPARalpha expression in patients with dilated cardiomyopathy. Eur J Heart Fail, 2006, 8(3): 290-294

[10] Fabregat-AndrésÓ, TierrezA, MataM, et al.. Induction of PGC-1α expression can be detected in blood samples of patients with ST-segment elevation acute myocardial infarction. PLoS One, 2011, 6(11): e26913

[11] ZhlobaAA, SubbotinaTF, AlekseevskayaES, et al.. The level of circulating PGC-1α in cardiovascular diseases. Biomed Khim, 2016, 62(2): 198-205 Russian)

[12] HeSL, TanWH, ZhangZT, et al.. Mitochondrial-related gene expression profiles suggest an important role of PGC-1alpha in the compensatory mechanism of endemic dilated cardiomyopathy. Exp Cell Res, 2013, 319(17): 2604-2616

[13] GarnierA, FortinD, DeloménieC, et al.. Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. J Physiol, 2003, 551(Pt2): 491-501

[14] SihagS, CresciS, LiAY, et al.. PGC-1alpha and ERRalpha target gene downregulation is a signature of the failing human heart. J Mol Cell Cardiol, 2009, 46(2): 201-212

[15] Xiao J. Study on the regulation mechanism of NO signaling pathway in mitochondrial biosynthesis of chronic hypoxia myocardial. The Third Military Medical University (Chinese), 2008

[16] HashimotoT, HussienR, OommenS, et al.. Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis. FASEB J, 2007, 21(10): 2602-2612

[17] LeeHC, YinPH, ChiCW, et al.. Increase in mitochondrial mass in human fibroblasts under oxidative stress and during replicative cell senescence. J Biomed Sci, 2002, 9(6Pt1): 517-526

[18] St-PierreJ, DroriS, UldryM, et al.. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 2006, 127(2): 397-408

[19] TurkiehA, CaubèreC, BarutautM, et al.. Apolipoprotein O is mitochondrial and promotes lipotoxicity in heart. J Clin Invest, 2014, 124(5): 2277-2286

[20] LeeSK, LeeJO, KimJH, et al.. Coenzyme Q10 increases the fatty acid oxidation through AMPK-mediated PPARα induction in 3T3-L1 preadipocytes. Cell Signal, 2012, 24(12): 2329-2336

[21] MerialC, BouloumieA, TrocherisV, et al.. Nitric oxide-dependent downregulation of adipocyte UCP-2 expression by tumor necrosis factor-α. Am J Physiol Cell Physiol, 2000, 279(4): C1100-C1106

[22] DrögeW. Free radicals in the physiological control of cell function. Physiol Rev, 2002, 82(1): 47-95

[23] ZhangX, LiL, PrabhakaranK, et al.. Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARα activation and oxidative stress. Toxicol Appl Pharmacol, 2007, 223(1): 10-19

[24] HopkinsWE, ChenZY, FukagawaNK, et al.. Increased atrial and brain natriuretic peptides in adults with cyanotic congenital heart disease: enhanced understanding of the relationship between hypoxia and natriuretic peptide secretion. Circulation, 2004, 109(23): 2872-2877

[25] HouLZ, ZhaoY, YangTS. Characteristics of serum and myocardial zymograms in rats fed with grains of Keshan disease area. Endemic Dis Bull, 1985, 6(1): 29-30(Chinese)

[26] YangX, FengL, ZhangY, et al.. Co-exposure of silica nanoparticles and methylmercury induced cardiac toxicity in vitro and in vivo. Sci Total Environ, 2018, 631–632: 811-821

[27] LiW, LiW, LengY, et al.. Ferroptosis is involved in diabetes myocardial ischemia/reperfusion injury through endoplasmic reticulum stress. DNA Cell Biol, 2020, 39(2): 210-225

[28] HoushmandF, FaghihiM, ZahediaslS. Role of atrial natriuretic peptide in oxytocin induced cardioprotection. Heart Lung Circ, 2015, 24(1): 86-93

[29] ProsserHC, ForsterME, RichardsAM, et al.. Urotensin II and urotensin II-related peptide (URP) in cardiac ischemia-reperfusion injury. Peptides, 2008, 29(5): 770-777

[30] SilvaJAJr, AraujoRC, BaltatuO, et al.. Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene. FASEB J, 2000, 14(13): 1858-1860

[31] Zhu MY. Investigation on PI3K/Akt/NO signaling pathway involves in the protective effect of bradykinin against doxorubicin-induced myocardial cell damage. Hebei Medical University (Chinese), 2016