Skip to main content
Log in

Valsartan regulates TGF-β/Smads and TGF-β/p38 pathways through lncRNA CHRF to improve doxorubicin-induced heart failure

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

This study investigated the interaction among valsartan (VAL), TGF-β pathways, and long non-coding RNA (lncRNA) cardiac hypertrophy-related factor (CHRF) in doxorubicin (DOX)-induced heart failure (HF), and explored their roles in DOX-induced HF progression. HF mice models in vivo were constructed by DOX induction. The expression of CHRF and TGF-β1 in hearts was detected, along with cardiac function, caspase-3 activity, and cell apoptosis. Primary myocardial cells were pretreated with VAL, followed by DOX induction in vitro for functional studies, including the detection of cell apoptosis with terminal deoxynucleotidyl transferase dUTP nick-end labeling and the expression of proteins associated with TGF-β1 pathways. HF models were established in vivo and in vitro. Expression of CHRF and TGF-β1 was up-regulated, and cell apoptosis and caspase-3 activity were increased in the hearts and cells of the HF models. VAL supplementation alleviated the cardiac dysfunction and injury in the HF process. Moreover, overexpressed CHRF up-regulated TGF-β1, promoted myocardial cell apoptosis, and reversed VAL’s cardiac protective effect, while interference of CHRF (si-CHRF) did the opposite. Down-regulation of CHRF reversed the increased expression of TGF-β1 and the downstream proteins induced by pcDNA-TGF-β1 in HL-1 cells, while overexpression of CHRF reversed the VAL’s cardiac protective effect in vivo. In conclusion, VAL regulates TGF-β pathways through lncRNA CHRF to improve DOX-induced HF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Akashiba A, Ono H, Ono Y, Ishimitsu T, Matsuoka H (2008) Valsartan improves L-NAME-exacerbated cardiac fibrosis with TGF-ß inhibition and apoptosis induction in spontaneously hypertensive rats. J Cardiol 52:239–246

    Article  PubMed  Google Scholar 

  • Albini A, Pennesi G, Donatelli F, Cammarota R, Flora SD, Noonan DM (2010) Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst 102:14–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Behnes M, Hoffmann U, Lang S, Weiss C, Ahmadnejad P, Neumaier M, Borggrefe M, Brueckmann M (2011) Transforming growth factor beta 1 (TGF-beta 1) in atrial fibrillation and acute congestive heart failure. Clin Res Cardiol 100:335–342

    Article  CAS  PubMed  Google Scholar 

  • Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, Tramontano A, Bozzoni I (2011) A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147:358–369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaplin S (2016) Sacubitril/valsartan for the treatment of heart failure. Prescriber 27:56–57

    Article  Google Scholar 

  • Dhingra R, Margulets V, Chowdhury SR, Thliveris J, Jassal D, Fernyhough P, Nd DG, Kirshenbaum LA (2014) Bnip3 mediates doxorubicin-induced cardiac myocyte necrosis and mortality through changes in mitochondrial signaling. Proc Natl Acad Sci USA 111:5537–5544

    Article  Google Scholar 

  • Gu M, Zheng A, Tu W, Zhao J, Li L, Li M, Han S, Hu X, Zhu J, Pan Y (2016) Circulating LncRNAs as novel, non-invasive biomarkers for prenatal detection of fetal congenital heart defects. Cell Physiol Biochem 38:1459–1471

    Article  CAS  PubMed  Google Scholar 

  • Houser SR, Margulies KB, Murphy AM, Spinale FG, Francis GS, Prabhu SD, Rockman HA, Kass DA, Molkentin JD, Sussman MA (2012) Animal models of heart failure: a scientific statement from the American Heart Association. Circ Res 111:131–150

    Article  CAS  PubMed  Google Scholar 

  • Ieronimakis N, Hays AL, Janebodin K, Mahoney WM, Duffield JS, Majesky MW, Reyes M (2013) Coronary adventitial cells are linked to perivascular cardiac fibrosis via TGFβ1 signaling in the mdx mouse model of Duchenne muscular dystrophy. J Mol Cell Cardiol 63:122–134

    Article  CAS  PubMed  Google Scholar 

  • Ikeuchi M, Tsutsui H, Shiomi T, Matsusaka H, Matsushima S, Wen J, Kubota T, Takeshita A (2004) Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction. Cardiovasc Res 64:526–535

    Article  CAS  PubMed  Google Scholar 

  • Jain A, Kishore K (2013) Doxorubicin-induced dilated cardiomyopathy for modified radical mastectomy: a case managed under cervical epidural anaesthesia. Indian J Anaesth 57:185–187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jasmin JF, Calderone A, Leung TK, Villeneuve L, Dupuis J (2003) Lung structural remodeling and pulmonary hypertension after myocardial infarction: complete reversal with irbesartan. Cardiovasc Res 58:621–631

    Article  CAS  PubMed  Google Scholar 

  • Jiao B, Wang YS, Cheng YN, Gao JJ, Zhang QZ (2011) Valsartan attenuated oxidative stress, decreased MCP-1 and TGF-β1 expression in glomerular mesangial and epithelial cells induced by high-glucose levels. Biosci Trends 5:173–181

    Article  CAS  PubMed  Google Scholar 

  • Kanduri C (2011) Kcnq1ot1: a chromatin regulatory RNA. Semin Cell Dev Biol 22:343–350

    Article  CAS  PubMed  Google Scholar 

  • Kapur NK, Wilson S, Yunis AA, Qiao X, Mackey E, Paruchuri V, Baker C, Aronovitz MJ, Karumanchi SA, Letarte M (2012) Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure. Circulation 125:2728–2738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keating GM, McCormack PL (2016) Sacubitril/valsartan in chronic heart failure with reduced ejection fraction: a guide to its use. Drugs Ther Perspect 33:1–7

    Article  Google Scholar 

  • Kolosova I, Nethery D, Kern JA (2011) Role of Smad2/3 and p38 MAP kinase in TGF-beta1-induced epithelial-mesenchymal transition of pulmonary epithelial cells. J Cell Physiol 226:1248–1254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumarswamy R, Bauters C, Volkmann I, Maury F, Fetisch J, Holzmann A, Lemesle G, De GP, Pinet F, Thum T (2014) Circulating long noncoding RNA, LIPCAR, predicts survival in patients with heart failure. Circ Res 114:1569–1575

    Article  CAS  PubMed  Google Scholar 

  • Leight JL, Wozniak MA, Chen S, Lynch ML, Chen CS (2012) Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition. Mol Biol Cell 23:781–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang WC, Fu WM, Wong CW, Wang Y, Wang WM, Hu GX, Zhang L, Xiao LJ, Wan DC, Zhang JF, Waye MM (2015) The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer. Oncotarget 6:22513–22525

    PubMed  PubMed Central  Google Scholar 

  • Maggioni AP, Latini R, Carson PE, Singh SN, Barlera S, Glazer R, Masson S, Cerè E, Tognoni G, Cohn JN (2005) Val-HeFT Investigators. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J 149:548–557

    Article  CAS  PubMed  Google Scholar 

  • Majani G, Giardini A, Opasich C, Glazer R, Hester A, Tognoni G, Cohn JN, Tavazzi L (2005) Effect of valsartan on quality of life when added to usual therapy for heart failure: results from the Valsartan Heart Failure Trial. J Card Fail 11:253–259

    Article  CAS  PubMed  Google Scholar 

  • Nakamae H, Tsumura K, Terada Y, Nakane T, Nakamae M, Ohta K, Yamane T, Hino M (2015) Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Cancer 104:2492–2498

    Article  Google Scholar 

  • Negmadjanov U, Holmuhamedov A, Emelyanova L, Xu H, Rizvi F, Ross GR, Tajik AJ, Shi Y, Holmuhamedov E, Jahangir A (2016) TGF-β1 increases resistance of NIH/3T3 fibroblasts toward apoptosis through activation of Smad2/3 and Erk1/2 pathways. J Patient Cent Res Rev 3:187–198

    Article  Google Scholar 

  • Porter AG, Janicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6:99–104

    Article  CAS  PubMed  Google Scholar 

  • Subeq YM, Ke CY, Lin NT, Lee CJ, Chiu YH, Hsu BG (2011) Valsartan decreases TGF-β1 production and protects against chlorhexidine digluconate-induced liver peritoneal fibrosis in rats. Cytokine 53:223–230

    Article  CAS  PubMed  Google Scholar 

  • Sui X, Zheng J, Yao Q (2016) Obestatin improves doxorubicin-induced heart failure via the regulation of the Lncrna Mhrt on Nrf2. Lipid Cardiovasc Res 2:17–26

    Google Scholar 

  • Sun M, Gadad SS, Kim DS, Kraus WL (2015) Discovery, annotation, and functional analysis of long noncoding RNAs controlling cell-cycle gene expression and proliferation in breast cancer cells. Mol Cell 59:698–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun Z, Schriewer J, Tang M, Marlin J, Taylor F, Shohet RV, Konorev EA (2016) The TGF-β pathway mediates doxorubicin effects on cardiac endothelial cells. J Mol Cell Cardiol 90:129–138

    Article  CAS  PubMed  Google Scholar 

  • Viereck J, Kumarswamy R, Foinquinos A, Xiao K, Avramopoulos P, Kunz M, Dittrich M, Maetzig T, Zimmer K, Remke J (2016) Long noncoding RNA Chast promotes cardiac remodeling. Sci Transl Med 8:326ra22

    Article  PubMed  Google Scholar 

  • Villar AV, García R, Llano M, Cobo M, Merino D, Lantero A, Tramullas M, Hurlé JM, Hurlé MA, Nistal JF (2013) BAMBI (BMP and activin membrane-bound inhibitor) protects the murine heart from pressure-overload biomechanical stress by restraining TGF-β signaling. Biochim Biophys Acta 1832:323–335

    Article  CAS  PubMed  Google Scholar 

  • Wang S, Zhong Z, Wan J, Tan W, Wu G, Chen M, Wang Y (2013) Oridonin induces apoptosis, inhibits migration and invasion on highly-metastatic human breast cancer cells. Am J Chin Med 41:177–196

    Article  PubMed  Google Scholar 

  • Wang K, Liu F, Zhou LY, Long B, Yuan SM, Wang Y, Liu CY, Sun T, Zhang XJ, Li PF (2014) The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489. Circ Res 114:1377–1388

    Article  CAS  PubMed  Google Scholar 

  • Wang K, Liu CY, Zhou LY, Wang JX, Wang M, Zhao B, Zhao WK, Xu SJ, Fan LH, Zhang XJ, Feng C, Wang CQ, Zhao YF, Li PF (2015) APF lncRNA regulates autophagy and myocardial infarction by targeting miR-188-3p. Nat Commun 6:6779

    Article  CAS  PubMed  Google Scholar 

  • Wu Q, Han L, Yan W, Ji X, Han R, Yang J, Yuan J, Ni C (2016) miR-489 inhibits silica-induced pulmonary fibrosis by targeting MyD88 and Smad3 and is negatively regulated by lncRNA CHRF. Sci Rep 6:30921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu H, Liu C, Rao S, He L, Zhang T, Sun S, Wu B, Zou L, Wang S, Xue Y, Jia T, Zhao S, Li G, Liu S, Li G, Liang S (2016) LncRNA NONRATT021972 siRNA rescued decreased heart rate variability in diabetic rats in superior cervical ganglia. Auton Neurosci 201:1–7

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chun-Guang Qiu.

Ethics declarations

Conflicts of interest

The authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, L., Yan, KP., Liu, XC. et al. Valsartan regulates TGF-β/Smads and TGF-β/p38 pathways through lncRNA CHRF to improve doxorubicin-induced heart failure. Arch. Pharm. Res. 41, 101–109 (2018). https://doi.org/10.1007/s12272-017-0980-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-017-0980-4

Keywords

Navigation