Login Register Cart 0
Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

Protein PDK4 Interacts with HMGCS2 to Facilitate High Glucoseinduced Myocardial Injuries

Author(s): Wenliang Tan, Huogeng Bao, Ziming Liu, Yuanyuan Liu, Lang Hong and Liang Shao*

Volume 23, Issue 10, 2023

Published on: 23 November, 2022

Page: [1104 - 1115] Pages: 12

DOI: 10.2174/1566524023666221021124202

Price: $65

Open Access Journals Promotions 2
conference banner
Abstract

Objectives: As a distinct type of cardiomyopathy, diabetic cardiomyopathy (DCM) is featured as diastolic or systolic cardiac dysfunction in diabetic patients. In order to broaden the understanding of molecular mechanisms in DCM, we intended to explore the mechanism of the interaction between PDK4 protein and Hmgcs2 in high glucose (HG)-induced myocardial damage.

Methods: PDK4 and Hmgcs2 expression in the myocardium of diabetes mellitus (DM) model rats and HG-incubated cardiomyocyte line H9C2 was analyzed by western blot analysis. Echocardiography and TUNEL assay were utilized for respective assessment of cardiac structure and function and cardiomyocyte apoptosis in DM rats after silencing PDK4 or/and Hmgcs2. In vitro, the impact of PDK4 and Hmgcs2 on HG-induced cardiomyocyte injuries was identified with cell counting kit-8 and flow cytometry assays, along with detection of LDH release, caspase-3/7 activities, and reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Moreover, a coimmunoprecipitation assay was utilized to test the interaction between PDK4 and Hmgcs2.

Results: Both PDK4 and Hmgcs2 were highly expressed in the myocardial tissues of DM rats. Mechanistically, PDK4 interacted with Hmgcs2 to upregulate Hmgcs2 expression in HG-induced H9C2 cells. Silencing PDK4 improved cardiac function and reduced cardiomyocyte apoptosis in DM rats. In HG-induced H9C2 cells, PDK4 or Hmgcs2 silencing enhanced cell viability and reduced LDH release, caspase-3/7 activities, cell apoptosis, and ROS and MDA levels, and these trends were further promoted by the simultaneous silencing of PDK4 and Hmgcs2.

Conclusion: In summary, the silencing of PDK4 and Hmgcs2 alleviated HG-induced myocardial injuries through their interaction.

Keywords: Diabetes mellitus, PDK4, Hmgcs2, protein interaction, cell apoptosis, myocardial injuries.

« Previous Next »
[1]
Murtaza G, Virk HUH, Khalid M, et al. Diabetic cardiomyopathy - A comprehensive updated review. Prog Cardiovasc Dis 2019; 62(4): 315-26.
[http://dx.doi.org/10.1016/j.pcad.2019.03.003] [PMID: 30922976]
[2]
Evangelista I, Nuti R, Picchioni T, Dotta F, Palazzuoli A. Molecular dysfunction and phenotypic derangement in diabetic cardi-omyopathy. Int J Mol Sci 2019; 20(13): 3264.
[http://dx.doi.org/10.3390/ijms20133264] [PMID: 31269778]
[3]
Paolillo S, Marsico F, Prastaro M, et al. Diabetic cardiomyopathy. Heart Fail Clin 2019; 15(3): 341-7.
[http://dx.doi.org/10.1016/j.hfc.2019.02.003] [PMID: 31079692]
[4]
Jia G, Whaley-Connell A, Sowers JR. Diabetic cardiomyopathy: A hyperglycaemia- and insulin-resistance-induced heart dis-ease. Diabetologia 2018; 61(1): 21-8.
[http://dx.doi.org/10.1007/s00125-017-4390-4] [PMID: 28776083]
[5]
Dillmann WH. Diabetic cardiomyopathy. Circ Res 2019; 124(8): 1160-2.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.314665] [PMID: 30973809]
[6]
Al Kury LT. Calcium homeostasis in ventricular myocytes of diabetic cardiomyopathy. J Diabetes Res 2020; 2020: 1942086.
[7]
Xia YW, Wang SB, Xiao LH. Long noncoding RNA PVT1 facilitates high glucose‐induced cardiomyocyte death through the miR‐23a‐3p/CASP10 axis. Cell Biol Int 2021; 45(1): 154-63.
[http://dx.doi.org/10.1002/cbin.11479] [PMID: 33049089]
[8]
Yu LM, Dong X, Xue XD, et al. Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ische-mia‐reperfusion injury by improving mitochondrial quality control: Role of SIRT6. J Pineal Res 2021; 70(1): e12698.
[http://dx.doi.org/10.1111/jpi.12698] [PMID: 33016468]
[9]
Burdick J, Sun Z. Pyruvate dehydrogenase kinase 4: A key mediator for metabolic regulation of liver regeneration. Hepatol Commun 2020; 4(4): 475-7.
[http://dx.doi.org/10.1002/hep4.1506] [PMID: 32258943]
[10]
Chistiakov DA, Orekhov AN, Bobryshev YV. The impact of FOXO-1 to cardiac pathology in diabetes mellitus and diabetes-related metabolic abnormalities. Int J Cardiol 2017; 245: 236-44.
[11]
Li T, Xu J, Qin X, et al. Glucose oxidation positively regulates glucose uptake and improves cardiac function recovery after myocardial reperfusion. Am J Physiol Endocrinol Metab 2017; 313(5): E577-85.
[http://dx.doi.org/10.1152/ajpendo.00014.2017] [PMID: 28325730]
[12]
Dai L, Xie Y, Zhang W, et al. Weighted gene co-expression network analysis identifies angptl4 as a key regulator in diabetic cardiomyopathy via FAK/SIRT3/ROS pathway in cardiomyocyte. Front Endocrinol 2021; 12: 705154.
[13]
Fang L, Li TS, Zhang JZ, et al. Fructose drives mitochondrial metabolic reprogramming in podocytes via Hmgcs2-stimulated fatty acid degradation. Signal Transduct Target Ther 2021; 6(1): 253.
[http://dx.doi.org/10.1038/s41392-021-00570-y] [PMID: 34238920]
[14]
Lindsay RT, Dieckmann S, Krzyzanska D, et al. β-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery. eLife 2021; 10: e71270.
[http://dx.doi.org/10.7554/eLife.71270] [PMID: 34491199]
[15]
Feng Y, Xu W, Zhang W, Wang W, Liu T, Zhou X. LncRNA DCRF regulates cardiomyocyte autophagy by targeting miR-551b-5p in diabetic cardiomyopathy. Theranostics 2019; 9(15): 4558-66.
[http://dx.doi.org/10.7150/thno.31052] [PMID: 31285779]
[16]
Wang L, Bi X, Han J. Silencing of peroxisome proliferator‐activated receptor‐alpha alleviates myocardial injury in diabetic cardiomyopathy by downregulating 3‐hydroxy-3-methylglutaryl-coenzyme A synthase 2 expression. IUBMB Life 2020; 72(9): 1997-2009.
[http://dx.doi.org/10.1002/iub.2337] [PMID: 32734614]
[17]
Wu X, Zhou X, Lai S, Liu J, Qi J. Curcumin activates Nrf2/HO -1 signaling to relieve diabetic cardiomyopathy injury by reduc-ing ROS in vitro and in vivo. FASEB J 2022; 36(9): e22505.
[http://dx.doi.org/10.1096/fj.202200543RRR] [PMID: 35971779]
[18]
Wang J, Wang R, Li J, Yao Z. Rutin alleviates cardiomyocyte injury induced by high glucose through inhibiting apoptosis and endoplasmic reticulum stress. Exp Ther Med 2021; 22(3): 944.
[http://dx.doi.org/10.3892/etm.2021.10376] [PMID: 34306208]
[19]
Zhu HZ, Zhang LY, Zhai ME, et al. GDF11 alleviates pathological myocardial remodeling in diabetic cardiomyopathy through sirt1-dependent regulation of oxidative stress and apoptosis. Front Cell Dev Biol 2021; 9: 686848.
[http://dx.doi.org/10.3389/fcell.2021.686848]
[20]
Lombardi C, Spigoni V, Gorga E, Dei Cas A. Novel insight into the dangerous connection between diabetes and heart failure. Herz 2016; 41(3): 201-7.
[http://dx.doi.org/10.1007/s00059-016-4415-7] [PMID: 27071966]
[21]
Zhao D, Yang J, Yang L. Insights for oxidative stress and mtor signaling in myocardial ischemia/reperfusion injury under dia-betes. Oxid Med Cell Longev 2017; 2017: 6437467.
[22]
Bhagani H, Nasser SA, Dakroub A, et al. The mitochondria: A target of polyphenols in the treatment of diabetic cardiomyopa-thy. Int J Mol Sci 2020; 21(14): 4962.
[http://dx.doi.org/10.3390/ijms21144962] [PMID: 32674299]
[23]
Li N, Zhou H. SGLT2 inhibitors: A novel player in the treatment and prevention of diabetic cardiomyopathy. Drug Des Devel Ther 2020; 14: 4775-88.
[http://dx.doi.org/10.2147/DDDT.S269514]
[24]
Yu S, Dong B, Fang Z, Hu X, Tang L, Zhou S. Knockdown of lnc RNA AK 139328 alleviates myocardial ischaemia/reperfusion injury in diabetic mice via modulating miR‐204‐3p and inhibiting autophagy. J Cell Mol Med 2018; 22(10): 4886-98.
[http://dx.doi.org/10.1111/jcmm.13754] [PMID: 30047214]
[25]
Dede E, Liapis D, Davos C, et al. The effects of exercise training on cardiac matrix metalloproteinases activity and cardiac function in mice with diabetic cardiomyopathy. Biochem Biophys Res Commun 2022; 586: 8-13.
[http://dx.doi.org/10.1016/j.bbrc.2021.11.013]
[26]
Zhi SM, Fang GX, Xie XM, et al. Melatonin reduces OGD/R-induced neuron injury by regulating redox/inflammation/apoptosis signaling. Eur Rev Med Pharmacol Sci 2020; 24(3): 1524-36.
[PMID: 32096202]
[27]
Song S, Ding Y, Dai G, et al. Sirtuin 3 deficiency exacerbates diabetic cardiomyopathy via necroptosis enhancement and NLRP3 activation. Acta Pharmacol Sin 2021; 42(2): 230-41.
[http://dx.doi.org/10.1038/s41401-020-0490-7] [PMID: 32770173]
[28]
Taabazuing CY, Okondo MC, Bachovchin DA. Pyroptosis and apoptosis pathways engage in bidirectional crosstalk in mono-cytes and macrophages. Cell Chem Biol 2017; 24(4): 507-514.e4.
[http://dx.doi.org/10.1016/j.chembiol.2017.03.009] [PMID: 28392147]
[29]
Zhang C, Yu H, Yang H, Liu B. Activation of PI3K/PKB/GSK‐3β signaling by sciadopitysin protects cardiomyocytes against high glucose‐induced oxidative stress and apoptosis. J Biochem Mol Toxicol 2021; 35(10): e22887.
[http://dx.doi.org/10.1002/jbt.22887] [PMID: 34392578]
[30]
Chen P, Miao Y, Yan P, Wang XJ, Jiang C, Lei Y. MiR‐455‐5p ameliorates HG‐induced apoptosis, oxidative stress and in-flammatory via targeting SOCS3 in retinal pigment epithelial cells. J Cell Physiol 2019; 234(12): 21915-24.
[http://dx.doi.org/10.1002/jcp.28755] [PMID: 31041827]
[31]
Ma WQ, Sun XJ, Zhu Y, Liu NF. PDK4 promotes vascular calcification by interfering with autophagic activity and metabolic reprogramming. Cell Death Dis 2020; 11(11): 991.
[http://dx.doi.org/10.1038/s41419-020-03162-w] [PMID: 33203874]
[32]
Bolfer L, Estrada AH, Larkin C, et al. Functional consequences of PDK4 deficiency in doberman pinscher fibroblasts. Sci Rep 2020; 10(1): 3930.
[http://dx.doi.org/10.1038/s41598-020-60879-6] [PMID: 32127618]
[33]
Rohm M, Savic D, Ball V, et al. Cardiac dysfunction and metabolic inflexibility in a mouse model of diabetes without dyslipidemia. Diabetes 2018; 67(6): 1057-67.
[http://dx.doi.org/10.2337/db17-1195] [PMID: 29610263]
[34]
Cardoso AC, Lam NT, Savla JJ, et al. Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression. Nat Metab 2020; 2(2): 167-78.
[http://dx.doi.org/10.1038/s42255-020-0169-x] [PMID: 32617517]
[35]
Yin Q, Wang P, Wu X. MicroRNA -148 alleviates cardiac dysfunction, immune disorders and myocardial apoptosis in Myocar-dial Ischemia-Reperfusion (MI/R) injury by targeting Pyruvate Dehydrogenase Kinase (PDK4). Bioengineered 2021; 12(1): 5552-65.
[http://dx.doi.org/10.1080/21655979.2021.1965812] [PMID: 34517782]
[36]
Sahraoui A, Dewachter C, Vegh G, et al. High fat diet altered cardiac metabolic gene profile in Psammomys obesus gerbils. Lipids Health Dis 2020; 19(1): 123.
[http://dx.doi.org/10.1186/s12944-020-01301-y] [PMID: 32493392]
[37]
Bekhite M, Gonzalez-Delgado A, Hubner S, et al. The role of ceramide accumulation in human induced pluripotent stem cell-derived cardiomyocytes on mitochondrial oxidative stress and mitophagy. Free Radic Biol Med 2021; 167: 66-80.
[http://dx.doi.org/10.1016/j.freeradbiomed.2021.02.016]
[38]
Zhang Z, Zhang HY, Zhang Y, Li H. Inactivation of the Ras/MAPK/PPARγ signaling axis alleviates diabetic mellitus-induced erectile dysfunction through suppression of corpus cavernosal endothelial cell apoptosis by inhibiting HMGCS2 expression. Endocrine 2019; 63(3): 615-31.
[http://dx.doi.org/10.1007/s12020-018-1810-2] [PMID: 30460485]
[39]
Shukla SK, Liu W, Sikder K, et al. HMGCS2 is a key ketogenic enzyme potentially involved in type 1 diabetes with high cardio-vascular risk. Sci Rep 2017; 7(1): 4590.
[http://dx.doi.org/10.1038/s41598-017-04469-z] [PMID: 28676675]
[40]
Chen D, Ruan X, Liu Y, He Y. HMGCS2 silencing attenuates high glucose-induced in vitro diabetic cardiomyopathy by increas-ing cell viability, and inhibiting apoptosis, inflammation, and oxidative stress. Bioengineered 2022; 13(5): 11417-29.
[http://dx.doi.org/10.1080/21655979.2022.2063222] [PMID: 35506308]

Rights & Permissions Print Cite
Article Metrics
60
2
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy