Role and mechanism of peroxisome proliferator-activated receptor gamma coactivator 1α in inhibiting aortic valve interstitial cell activation_West China Medical Journal

Authors：

Shancuoji ^1,2 ,  LI Junli ^1,2 ,  CHEN Mao ^1,2

1. Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LI Junli, Email: 787951246@qq.com; CHEN Mao, Email: hmaochen@vip.sina.com

Keywords：

Aortic stenosis; aortic valve interstitial cell activation; peroxisome proliferator-activated receptor gamma coactivator 1α; calcium/calmodulin-dependent protein kinase 1δ

DOI：

10.7507/1002-0179.202402173

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Objective To investigate the role and mechanism of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) in the activation of aortic valve interstitial cells (AVICs) in aortic stenosis. Methods Isolating primary AVICs and stimulating their activation with transforming growth factor β1 (TGF-β1, 30 ng/mL), the expression of PGC-1α was detected. The activation of AVICs induced by TGF-β1 was observed after overexpression of PGC-1α by adenovirus or inhibition of PGC-1α function by GW9662. The possible downstream molecular mechanism of PGC-1α in AVICs activation was screened. Finally, the phenotype was further verified in primary human AVICs. Results The expression of PGC-1α decreased after the activation of AVICs induced by TGF-β1 (control group: 1.00±0.18; 24 h: 0.31±0.10; 48 h: 0.32±0.06; 72 h: 0.20±0.07; P<0.05). Specific overexpression of PGC-1α by adenovirus inhibited the activation of AVICs induced by TGF-β1 stimulation (periostin: 3.17±0.64 vs. 1.45±0.54, P<0.05; α-smooth muscle actin: 0.77±0.11 vs. 0.28±0.06, P<0.05). On the contrary, inhibition of PGC-1α function by GW9662 promoted the activation of AVICs (periostin: 2.20±0.68 vs. 7.99±2.50, P<0.05). Subsequently, it was found that PGC-1α might inhibit the activation of AVICs through downregulating the expression of calcium/calmodulin-dependent protein kinase (CAMK1δ) (0.97±0.04 vs. 0.74±0.11, P<0.05), and downregulating the expression of CAMK1δ alleviated the activation of AVICs (periostin: 1.76±0.11 vs. 0.99±0.20, P<0.05). The possible mechanism was that the activation of mammalian target of rapamycin (mTOR) signaling pathway was inhibited by reducing the accumulation of reactive oxygen species (ROS) (778.3±139.4 vs. 159.3±43.2, P<0.05). Finally, the protective effect of PGC-1α overexpression was verified in the activated phenotype of human AVICs (periostin: 2.73±0.53 vs. 1.63±0.14, P<0.05; connective tissue growth factor: 1.27±0.04 vs. 0.48±0.09, P<0.05). Conclusions The expression of PGC-1α significantly decreases during the activation of AVICs induced by TGF-β1. The overexpression of PGC-1α significantly inhibites the activation of AVICs, suggesting that PGC-1α plays a protective role in the activation of AVICs. The possible mechanism is that PGC-1α can inhibit the activation of CAMK1δ-ROS-mTOR pathway. In conclusion, interventions based on PGC-1α expression levels are new potential therapeutic targets for aortic stenosis.

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3.	Tanase DM, Valasciuc E, Gosav EM, et al. Contribution of oxidative stress (OS) in calcific aortic valve disease (CAVD): from pathophysiology to therapeutic targets. Cells, 2022, 11(17): 2663.
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6.	Avvedimento M, Tang GHL. Transcatheter aortic valve replacement (TAVR): recent updates. Prog Cardiovasc Dis, 2021, 69: 73-83.
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9.	Fu M, Peng D, Lan T, et al. Multifunctional regulatory protein connective tissue growth factor (CTGF): a potential therapeutic target for diverse diseases. Acta Pharm Sin B, 2022, 12(4): 1740-1760.
10.	Fang M, Alfieri CM, Hulin A, et al. Loss of β-catenin promotes chondrogenic differentiation of aortic valve interstitial cells. Arterioscler Thromb Vasc Biol, 2014, 34(12): 2601-2608.
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13.	Garsen M, Buijsers B, Sol M, et al. Peroxisome proliferator-activated receptor ɣ agonist mediated inhibition of heparanase expression reduces proteinuria. EBioMedicine, 2023, 90: 104506.
14.	Rogers JD, Aguado BA, Watts KM, et al. Network modeling predicts personalized gene expression and drug responses in valve myofibroblasts cultured with patient sera. Proc Natl Acad Sci U S A, 2022, 119(8): e2117323119.
15.	Yutzey KE, Demer LL, Body SC, et al. Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease. Arterioscler Thromb Vasc Biol, 2014, 34(11): 2387-2393.
16.	Sritharen Y, Enriquez-Sarano M, Schaff HV, et al. Pathophysiology of aortic valve stenosis: is it both fibrocalcific and sex specific?. Physiology (Bethesda), 2017, 32(3): 182-196.
17.	Siudut J, Natorska J, Wypasek E, et al. Impaired fibrinolysis in patients with isolated aortic stenosis is associated with enhanced oxidative stress. J Clin Med, 2020(6): 2002.
18.	Das D, Holmes A, Murphy GA, et al. TGF-beta1-induced MAPK activation promotes collagen synthesis, nodule formation, redox stress and cellular senescence in porcine aortic valve interstitial cells. J Heart Valve Dis, 2013, 22(5): 621-630.
19.	Zhang Y, Shen L, Zhu H, et al. PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis. Ann Rheum Dis, 2020, 79(9): 1227-1233.
20.	Aubert G, Vega RB, Kelly DP. Perturbations in the gene regulatory pathways controlling mitochondrial energy production in the failing heart. Biochim Biophys Acta, 2013, 1833(4): 840-847.
21.	Waldman M, Cohen K, Yadin D, et al. Regulation of diabetic cardiomyopathy by caloric restriction is mediated by intracellular signaling pathways involving “SIRT1 and PGC-1α”. Cardiovasc Diabetol, 2018, 17(1): 111.
22.	Arany Z, Novikov M, Chin S, et al. Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1alpha. Proc Natl Acad Sci U S A, 2006, 103(26): 10086-10091.
23.	Rodgers JT, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature, 2005, 434(7029): 113-118.
24.	Xiong S, Salazar G, Patrushev N, et al. Peroxisome proliferator-activated receptor γ coactivator-1α is a central negative regulator of vascular senescence. Arterioscler Thromb Vasc Biol, 2013, 33(5): 988-998.
25.	Fierro-Fernández M, Miguel V, Márquez-Expósito L, et al. MiR-9-5p protects from kidney fibrosis by metabolic reprogramming. FASEB J, 2020, 34(1): 410-431.
26.	Puigserver P, Adelmant G, Wu Z, et al. Activation of PPARgamma coactivator-1 through transcription factor docking. Science, 1999, 286(5443): 1368-1371.
27.	Akizuki K, Kinumi T, Ono A, et al. Autoactivation of C-terminally truncated Ca²⁺/calmodulin-dependent protein kinase (CaMK) Iδ via CaMK kinase-independent autophosphorylation. Arch Biochem Biophys, 2019, 668: 29-38.
28.	Luo X, Yu W, Liu Z, et al. Ageing increases cardiac electrical remodelling in rats and mice via NOX4/ROS/CaMKII-mediated calcium signalling. Oxid Med Cell Longev, 2022, 2022: 8538296.
29.	Hagler MA, Hadley TM, Zhang H, et al. TGF-β signalling and reactive oxygen species drive fibrosis and matrix remodelling in myxomatous mitral valves. Cardiovasc Res, 2013, 99(1): 175-184.
30.	Li X, Wang B, Tang L, et al. GSTA1 expression is correlated with aldosterone level in KCNJ5-mutated adrenal aldosterone-producing adenoma. J Clin Endocrinol Metab, 2018, 103(3): 813-823.
31.	Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev, 2004, 18(16): 1926-1945.
32.	Lu Y, Zhang Y, Pan Z, et al. Potential “therapeutic” effects of tocotrienol-rich fraction (trf) and carotene “against” bleomycin-induced pulmonary fibrosis in rats via TGF-β/Smad, PI3K/Akt/mTOR and NF-κB signaling pathways. Nutrients, 2022, 14(5): 1094.

1. Carabello BA. Introduction to aortic stenosis. Circ Res, 2013, 113(2): 179-185.
2. Peeters FECM, Meex SJR, Dweck MR, et al. Calcific aortic valve stenosis: hard disease in the heart: a biomolecular approach towards diagnosis and treatment. Eur Heart J, 2018, 39(28): 2618-2624.
3. Tanase DM, Valasciuc E, Gosav EM, et al. Contribution of oxidative stress (OS) in calcific aortic valve disease (CAVD): from pathophysiology to therapeutic targets. Cells, 2022, 11(17): 2663.
4. Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab, 2005, 1(6): 361-370.
5. Chen HJ, Pan XX, Ding LL, et al. Cardiac fibroblast-specific knockout of PGC-1α accelerates AngⅡ-induced cardiac remodeling. Front Cardiovasc Med, 2021, 8: 664626.
6. Avvedimento M, Tang GHL. Transcatheter aortic valve replacement (TAVR): recent updates. Prog Cardiovasc Dis, 2021, 69: 73-83.
7. Tavares CDJ, Aigner S, Sharabi K, et al. Transcriptome-wide analysis of PGC-1α-binding RNAs identifies genes linked to glucagon metabolic action. Proc Natl Acad Sci U S A, 2020, 117(36): 22204-22213.
8. Kim KK, Sheppard D, Chapman HA. TGF-β1 signaling and tissue fibrosis. Cold Spring Harb Perspect Biol, 2018, 10(4): a022293.
9. Fu M, Peng D, Lan T, et al. Multifunctional regulatory protein connective tissue growth factor (CTGF): a potential therapeutic target for diverse diseases. Acta Pharm Sin B, 2022, 12(4): 1740-1760.
10. Fang M, Alfieri CM, Hulin A, et al. Loss of β-catenin promotes chondrogenic differentiation of aortic valve interstitial cells. Arterioscler Thromb Vasc Biol, 2014, 34(12): 2601-2608.
11. Worke LJ, Barthold JE, Seelbinder B, et al. Densification of type Ⅰ collagen matrices as a model for cardiac fibrosis. Adv Healthc Mater, 2017, 6(22): 170014.
12. Oveissi F, Naficy S, Lee A, et al. Materials and manufacturing perspectives in engineering heart valves: a review. Mater Today Bio, 2019, 5: 100038.
13. Garsen M, Buijsers B, Sol M, et al. Peroxisome proliferator-activated receptor ɣ agonist mediated inhibition of heparanase expression reduces proteinuria. EBioMedicine, 2023, 90: 104506.
14. Rogers JD, Aguado BA, Watts KM, et al. Network modeling predicts personalized gene expression and drug responses in valve myofibroblasts cultured with patient sera. Proc Natl Acad Sci U S A, 2022, 119(8): e2117323119.
15. Yutzey KE, Demer LL, Body SC, et al. Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease. Arterioscler Thromb Vasc Biol, 2014, 34(11): 2387-2393.
16. Sritharen Y, Enriquez-Sarano M, Schaff HV, et al. Pathophysiology of aortic valve stenosis: is it both fibrocalcific and sex specific?. Physiology (Bethesda), 2017, 32(3): 182-196.
17. Siudut J, Natorska J, Wypasek E, et al. Impaired fibrinolysis in patients with isolated aortic stenosis is associated with enhanced oxidative stress. J Clin Med, 2020(6): 2002.
18. Das D, Holmes A, Murphy GA, et al. TGF-beta1-induced MAPK activation promotes collagen synthesis, nodule formation, redox stress and cellular senescence in porcine aortic valve interstitial cells. J Heart Valve Dis, 2013, 22(5): 621-630.
19. Zhang Y, Shen L, Zhu H, et al. PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis. Ann Rheum Dis, 2020, 79(9): 1227-1233.
20. Aubert G, Vega RB, Kelly DP. Perturbations in the gene regulatory pathways controlling mitochondrial energy production in the failing heart. Biochim Biophys Acta, 2013, 1833(4): 840-847.
21. Waldman M, Cohen K, Yadin D, et al. Regulation of diabetic cardiomyopathy by caloric restriction is mediated by intracellular signaling pathways involving “SIRT1 and PGC-1α”. Cardiovasc Diabetol, 2018, 17(1): 111.
22. Arany Z, Novikov M, Chin S, et al. Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1alpha. Proc Natl Acad Sci U S A, 2006, 103(26): 10086-10091.
23. Rodgers JT, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature, 2005, 434(7029): 113-118.
24. Xiong S, Salazar G, Patrushev N, et al. Peroxisome proliferator-activated receptor γ coactivator-1α is a central negative regulator of vascular senescence. Arterioscler Thromb Vasc Biol, 2013, 33(5): 988-998.
25. Fierro-Fernández M, Miguel V, Márquez-Expósito L, et al. MiR-9-5p protects from kidney fibrosis by metabolic reprogramming. FASEB J, 2020, 34(1): 410-431.
26. Puigserver P, Adelmant G, Wu Z, et al. Activation of PPARgamma coactivator-1 through transcription factor docking. Science, 1999, 286(5443): 1368-1371.
27. Akizuki K, Kinumi T, Ono A, et al. Autoactivation of C-terminally truncated Ca²⁺/calmodulin-dependent protein kinase (CaMK) Iδ via CaMK kinase-independent autophosphorylation. Arch Biochem Biophys, 2019, 668: 29-38.
28. Luo X, Yu W, Liu Z, et al. Ageing increases cardiac electrical remodelling in rats and mice via NOX4/ROS/CaMKII-mediated calcium signalling. Oxid Med Cell Longev, 2022, 2022: 8538296.
29. Hagler MA, Hadley TM, Zhang H, et al. TGF-β signalling and reactive oxygen species drive fibrosis and matrix remodelling in myxomatous mitral valves. Cardiovasc Res, 2013, 99(1): 175-184.
30. Li X, Wang B, Tang L, et al. GSTA1 expression is correlated with aldosterone level in KCNJ5-mutated adrenal aldosterone-producing adenoma. J Clin Endocrinol Metab, 2018, 103(3): 813-823.
31. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev, 2004, 18(16): 1926-1945.
32. Lu Y, Zhang Y, Pan Z, et al. Potential “therapeutic” effects of tocotrienol-rich fraction (trf) and carotene “against” bleomycin-induced pulmonary fibrosis in rats via TGF-β/Smad, PI3K/Akt/mTOR and NF-κB signaling pathways. Nutrients, 2022, 14(5): 1094.

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Latest ArticlesRole and mechanism of peroxisome proliferator-activated receptor gamma coactivator 1α in inhibiting aortic valve interstitial cell activation

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