Document Type : Original Article

Authors

1 Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, ‎Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.

2 Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, ‎Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.

3 Department of Biotechnology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

4 Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, ‎Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.

Abstract

Background: Lots of people die from heart failure (HF) because of fibrosis formation. As injured myocytes deregulated MMP-2, MMP-4, TIMP-2, Ang, plasma renin activity  (PRA), and ACE leading to fibrosis, their regulation can improve HF. One of the most effective treatments for heart failure is the use of hAMSCs-CM, which has been shown to improve heart function and reduce symptoms. The study innovation was the investigation of the in vivo mode of action of hAMSCs-CM on HF fibrosis focusing on the mentioned proteins for the first time. We expected that this study partly fill the scientific gap in HF treatment.
Methods: Frothy rats were divided into 4 groups; Control, HF, culture medium, and CM. To induce HF, isoproterenol (ISO) was injected into all animals except for the control. CM were injected into the CM group and the culture medium group received culture medium. Then, cardiac functions were measured using echocardiography and serum fibrosis was evaluated by ELISA.
Results: HF model showed decreased MMP-2, MMP-4, Ang, PRA, and ACE and increased TIMP-2, whereas hAMSCs-CM therapy reversed them compared with controls.
Conclusion: Our result has partially filled the HF treatment’s gap as hAMSCs-CM improved cardiac function and reduced cardiac fibrosis and the serum fibrogenic proteins.

Keywords

Main Subjects

1.Daltro PS, Barreto BC, Silva P, Neto PC, Sousa Filho P, Neta DS, et al. Therapy with mesenchymal stromal cells or conditioned medium reverse cardiac alterations in a high-fat diet–induced obesity model. Cytotherapy. 2017;19(10):1176-88.
2.Roger VL. Epidemiology of heart failure: a contemporary perspective. Circulation research. 2021;128(10):1421-34.
3.Jain V, Minhas AMK, Morris AA, Greene SJ, Pandey A, Khan SS, et al. Demographic and Regional Trends of Heart Failure–Related Mortality in Young Adults in the US, 1999-2019. JAMA cardiology. 2022;7(9):900-4.
4.Zhou H, Yang H-X, Yuan Y, Deng W, Zhang J-Y, Bian Z-Y, et al. Paeoniflorin attenuates pressure overload-induced cardiac remodeling via inhibition of TGFβ/Smads and NF-κB pathways. Journal of Molecular Histology. 2013;44(3):357-67.
5.Slawik J, Adrian L, Hohl M, Lothschütz S, Laufs U, Böhm M. Irregular pacing of ventricular cardiomyocytes induces pro‐fibrotic signalling involving paracrine effects of transforming growth factor beta and connective tissue growth factor. European Journal of Heart Failure. 2019;21(4):482-91.
6.Castillero E, Akashi H, Najjar M, Ji R, Brandstetter LM, Wang C, et al. Activin type II receptor ligand signaling inhibition after experimental ischemic heart failure attenuates cardiac remodeling and prevents fibrosis. American Journal of Physiology-Heart and Circulatory Physiology. 2020;318(2):H378-H90.
7.Akahori H, Tsujino T, Naito Y, Matsumoto M, Sasaki N, Iwasaku T, et al. Atorvastatin ameliorates cardiac fibrosis and improves left ventricular diastolic function in hypertensive diastolic heart failure model rats. Journal of Hypertension. 2014;32(7):1534-41.
8.Markmee R, Aungsuchawan S, Narakornsak S, Tancharoen W, Bumrungkit K, Pangchaidee N, et al. Differentiation of mesenchymal stem cells from human amniotic fluid to cardiomyocyte‑like cells. Molecular medicine reports. 2017;16(5):6068-76.
9.Liguori TTA, Liguori GR, Moreira LFP, Harmsen MC. Adipose tissue–derived stromal cells’ conditioned medium modulates endothelial‐mesenchymal transition induced by IL‐1β/TGF‐β2 but does not restore endothelial function. Cell proliferation. 2019;52(6):e12629.
10.Chen T-J, Yeh Y-T, Peng F-S, Li A-H, Wu S-C. S100A8/A9 enhances immunomodulatory and tissue-repairing properties of human amniotic mesenchymal stem cells in myocardial ischemia-reperfusion injury. International journal of molecular sciences. 2021;22(20):11175.
11.Miceli V, Bertani A, Chinnici CM, Bulati M, Pampalone M, Amico G, et al. Conditioned medium from human amnion-derived mesenchymal stromal/stem cells attenuating the effects of cold ischemia-reperfusion injury in an in vitro model using human alveolar epithelial cells. International Journal of Molecular Sciences. 2021;22(2):510.
12.Jain M, Minocha E, Tripathy NK, Singh N, Chaturvedi CP, Nityanand S. Comparison of the cardiomyogenic potency of human amniotic fluid and bone marrow mesenchymal stem cells. International Journal of Stem Cells. 2019;12(3):449-56.
13.Razavi Tousi SMT, Sharifi M, Naseroleslami M, Azizi Y, Aboutaleb N. Mesenchymal Stem Cells Derived from Human Amniotic Membrane Increase VEGF and Extenuate Fibrosis in Heart Failure Rats. Iranian Journal of Science and Technology, Transactions A: Science. 2022;46(3):781-91.
14.Zeng Z, Xu L, Xu Y, Ruan Y, Liu D, Li J, et al. Normothermic Ex Vivo Heart Perfusion with Mesenchymal Stem Cell-Derived Conditioned Medium Improves Myocardial Tissue Protection in Rat Donation after Circulatory Death Hearts. Stem Cells International. 2022;2022.
15.Sivakumar P, Gupta S, Sarkar S, Sen S. Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy. Molecular and cellular biochemistry. 2008;307(1):159-67.
16.Squire IB, Evans J, Ng LL, Loftus IM, Thompson MM. Plasma MMP-9 and MMP-2 following acute myocardial infarction in man: correlation with echocardiographic and neurohumoral parameters of left ventricular dysfunction. Journal of cardiac failure. 2004;10(4):328-33.
17.Gonçalves PR, Nascimento LD, Gerlach RF, Rodrigues KE, Prado AF. Matrix metalloproteinase 2 as a pharmacological target in heart failure. Pharmaceuticals. 2022;15(8):920.
18.Martos R, Baugh J, Ledwidge M, O'Loughlin C, Murphy NF, Conlon C, et al. Diagnosis of heart failure with preserved ejection fraction: improved accuracy with the use of markers of collagen turnover. European journal of heart failure. 2009;11(2):191-7.
19.Kandalam V, Basu R, Abraham T, Wang X, Soloway PD, Jaworski DM, et al. TIMP2 deficiency accelerates adverse post–myocardial infarction remodeling because of enhanced MT1-MMP activity despite lack of MMP2 activation. Circulation research. 2010;106(4):796-808.
20.Webb CS, Bonnema DD, Ahmed SH, Leonardi AH, McClure CD, Clark LL, et al. Specific temporal profile of matrix metalloproteinase release occurs in patients after myocardial infarction: relation to left ventricular remodeling. Circulation. 2006;114(10):1020-7.
21.Park BE, Yang DH, Kim HJ, Park YJ, Kim HN, Jang SY, et al. Incremental predictive value of plasma renin activity as a prognostic biomarker in patients with heart failure. Journal of Korean Medical Science. 2020;35(42).
22.Azuma K, Nishimura K, Min K-D, Takahashi K, Matsumoto Y, Eguchi A, et al. Plasma renin activity variation following admission predicts patient outcome in acute decompensated heart failure with reduced and mildly reduced ejection fraction. Heliyon. 2023;9(2).
23.Chirinos JA, Cohen JB, Zhao L, Hanff T, Sweitzer N, Fang J, et al. Clinical and proteomic correlates of plasma ACE2(angiotensin-converting enzyme 2) in human heart failure. Hypertension. 2020;76(5):1526-36.
24.Sama IE, Ravera A, Santema BT, Van Goor H, Ter Maaten JM, Cleland JG, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors. European heart journal. 2020;41(19):1810-7.
25.Naseroleslami M, Aboutaleb N. Human amniotic membrane mesenchymal stem cells exert cardioprotective effects against isoproterenol(ISO)-induced myocardial injury through suppression of inflammation and modulation of inflammatory MAPK/NF-κB pathway. Cell and Tissue Banking. 2022;23(1):67-77.
26.Sharifi M, Nazarinia D, Ramezani F, Azizi Y, Naderi N, Aboutaleb N. Necroptosis and RhoA/ROCK pathways: molecular targets of Nesfatin-1 in cardioprotection against myocardial ischemia/reperfusion injury in a rat model. Molecular biology reports. 2021;48(3):2507-18.
27.Okada H, Takemura G, Kosai K-i, Li Y, Takahashi T, Esaki M, et al. Postinfarction gene therapy against transforming growth factor-β signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure. Circulation. 2005;111(19):2430-7.
28.Liu Y, Huang H, Xia W, Tang Y, Li H, Huang C. NADPH oxidase inhibition ameliorates cardiac dysfunction in rabbits with heart failure. Molecular and cellular biochemistry. 2010;343(1):143-53.
29.Lee AJ, Mahoney CM, Cai CC, Ichinose R, Stefani RM, Marra KG, et al. Sustained delivery of SB-431542, a type I transforming growth factor beta-1 receptor inhibitor, to prevent arthrofibrosis. Tissue Engineering Part A. 2021;27(21-22):1411-21.
30.Frangogiannis NG. The immune system and cardiac repair. Pharmacological research. 2008;58(2):88-111.
31.Timmers L, Lim SK, Hoefer IE, Arslan F, Lai RC, van Oorschot AA, et al. Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem cell research. 2011;6(3):206-14.
32.Chong JJ, Yang X, Don CW, Minami E, Liu Y-W, Weyers JJ, et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature. 2014;510(7504):273-7.
33.Perrone-Filardi P, Paolillo S, Agostoni P, Basile C, Basso C, Barillà F, et al. Renin-angiotensin-aldosterone system inhibition in patients affected by heart failure: efficacy, mechanistic effects and practical use of sacubitril/valsartan. Position Paper of the Italian Society of Cardiology. European Journal of Internal Medicine. 2022.
34.Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. New England Journal of Medicine. 1999;341(8):577-85.
35.Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang C-S, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction(SOLVD). Circulation. 1990;82(5):1724-9.
36.Gheorghiade M, Böhm M, Greene SJ, Fonarow GC, Lewis EF, Zannad F, et al. Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. Jama. 2013;309(11):1125-35.
37.Ueda T, Kawakami R, Nishida T, Onoue K, Soeda T, Okayama S, et al. Plasma renin activity is a strong and independent prognostic indicator in patients with acute decompensated heart failure treated with renin-angiotensin system inhibitors. Circulation Journal. 2015;79(6):1307-14.
38.Vaduganathan M, Cheema B, Cleveland E, Sankar K, Subacius H, Fonarow GC, et al. Plasma renin activity, response to aliskiren, and clinical outcomes in patients hospitalized for heart failure: the ASTRONAUT trial. European journal of heart failure. 2018;20(4):677-86.
39.Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M, et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 2012;487(7408):477-81.