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HIV Tat Protein Induces Myocardial Fibrosis Through TGF-β1-CTGF Signaling Cascade: A Potential Mechanism of HIV Infection-Related Cardiac Manifestations

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Abstract

Human immunodeficiency virus (HIV) infection is a risk factor of cardiovascular diseases (CVDs). HIV-infected patients exhibit cardiac dysfunction coupled with cardiac fibrosis. However, the reason why HIV could induce cardiac fibrosis remains largely unexplored. HIV-1 trans-activator of transcription (Tat) protein is a regulatory protein, which plays a critical role in the pathogenesis of various HIV-related complications. In the present study, recombinant Tat was administered to mouse myocardium or neonatal mouse cardiac fibroblasts in different doses. Hematoxylin–eosin and Masson’s trichrome staining were performed to observe the histological changes of mice myocardial tissues. EdU staining and MTS assay were used to evaluate the proliferation and viability of neonatal mouse cardiac fibroblasts, respectively. Real-time PCR and western blot analysis were used to detect CTGF, TGF-β1, and collagen I mRNA and protein expression levels, respectively. The results showed that Tat promoted the occurrence of myocardial fibrosis in mice. Also, we found that Tat increased the proliferative ability and the viability of neonatal mouse cardiac fibroblasts. The protein and mRNA expression levels of TGF-β1 and CTGF were significantly upregulated both in Tat-treated mouse myocardium and neonatal mouse cardiac fibroblasts. However, co-administration of TGF-β inhibitor abrogated the enhanced expression of collagen I induced by Tat in neonatal mouse cardiac fibroblasts. In conclusion, Tat contributes to HIV-related cardiac fibrosis through enhanced TGF-β1-CTGF signaling cascade.

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Abbreviations

CVD:

Cardiovascular disease

HIV:

Human immunodeficiency virus

HE staining:

Hematoxylin–eosin staining

I Kr :

HERG K+ current

QTc:

Corrected QT

Tat:

Trans-activator of transcription

TGF-β1:

Transforming growth factor-β1

References

  1. World Health Organization. Fact sheet on HIV/ AIDS. Retrieved July 30, 2017, from http://www.who.int/mediacentre/factsheets/fs360/en/.

  2. Feinstein, M. J., Bahiru, E., Achenbach, C., Longenecker, C. T., Hsue, P., So-Armah, K., Freiberg, M. S., & Lloyd-Jones, D. M. (2016). Patterns of cardiovascular mortality for HIV-infected adults in the United States: 1999 to 2013. The American Journal of Cardiology, 117, 214–220.

    Article  Google Scholar 

  3. Thiara, D. K., Liu, C. Y., Raman, F., Mangat, S., Purdy, J. B., Duarte, H. A., Schmidt, N., Hur, J., Sibley, C. T., Bluemke, D. A., & Hadigan, C. (2015). Abnormal myocardial function is related to myocardial steatosis and diffuse myocardial fibrosis in HIV-infected adults. The Journal of Infectious Diseases, 212, 1544–1551.

    Article  CAS  Google Scholar 

  4. d’Amati, G., di Gioia, C. R., & Gallo, P. (2001). Pathological findings of HIV-associated cardiovascular disease. Annals of the New York Academy of Sciences, 946, 23–45.

    Article  CAS  Google Scholar 

  5. Prendergast, B. D. (2003). HIV and cardiovascular medicine. Heart, 89, 793–800.

    Article  CAS  Google Scholar 

  6. deFilippi, C., Christenson, R., Joyce, J., Park, E. A., Wu, A., Fitch, K. V., Looby, S. E., Lu, M. T., Hoffmann, U., Grinspoon, S. K., & Lo, J. (2018). Brief report: Statin effects on myocardial fibrosis markers in people living with HIV. Journal of Acquired Immune Deficiency Syndromes, 78, 105–110.

    Article  CAS  Google Scholar 

  7. Shannon, R. P., Simon, M. A., Mathier, M. A., Geng, Y. J., Mankad, S., & Lackner, A. A. (2000). Dilated cardiomyopathy associated with simian AIDS in nonhuman primates. Circulation, 101, 185–193.

    Article  CAS  Google Scholar 

  8. Mak, I. T., Kramer, J. H., Chen, X., Chmielinska, J. J., Spurney, C. F., & Weglicki, W. B. (2013). Mg supplementation attenuates ritonavir-induced hyperlipidemia, oxidative stress, and cardiac dysfunction in rats. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 305, R1102-1111.

    Article  CAS  Google Scholar 

  9. Ahamed, J., Terry, H., Choi, M. E., & Laurence, J. (2016). Transforming growth factor-beta1-mediated cardiac fibrosis: Potential role in HIV and HIV/antiretroviral therapy-linked cardiovascular disease. AIDS, 30, 535–542.

    Article  Google Scholar 

  10. Debaisieux, S., Rayne, F., Yezid, H., & Beaumelle, B. (2012). The ins and outs of HIV-1 Tat. Traffic, 13, 355–363.

    Article  CAS  Google Scholar 

  11. Duan, M., Yao, H., Hu, G., Chen, X., Lund, A. K., & Buch, S. (2013). HIV Tat induces expression of ICAM-1 in HUVECs: implications for miR-221/-222 in HIV-associated cardiomyopathy. PLoS ONE, 8, e60170.

    Article  CAS  Google Scholar 

  12. Bai, Y. L., Liu, H. B., Sun, B., Zhang, Y., Li, Q., Hu, C. W., Zhu, J. X., Gong, D. M., Teng, X., Zhang, Q., Yang, B. F., & Dong, D. L. (2011). HIV Tat protein inhibits hERG K+ channels: A potential mechanism of HIV infection induced LQTs. Journal of Molecular and Cellular Cardiology, 51, 876–880.

    Article  CAS  Google Scholar 

  13. Raidel, S. M., Haase, C., Jansen, N. R., Russ, R. B., Sutliff, R. L., Velsor, L. W., Day, B. J., Hoit, B. D., Samarel, A. M., & Lewis, W. (2002). Targeted myocardial transgenic expression of HIV Tat causes cardiomyopathy and mitochondrial damage. American Journal of Physiology. Heart and Circulatory Physiology, 282, H1672-1678.

    Article  CAS  Google Scholar 

  14. Fang, Q., Kan, H., Lewis, W., Chen, F., Sharma, P., & Finkel, M. S. (2009). Dilated cardiomyopathy in transgenic mice expressing HIV Tat. Cardiovascular Toxicology, 9, 39–45.

    Article  CAS  Google Scholar 

  15. Yue, Y., Meng, K., Pu, Y., & Zhang, X. (2017). Transforming growth factor beta (TGF-beta) mediates cardiac fibrosis and induces diabetic cardiomyopathy. Diabetes Research and Clinical Practice, 133, 124–130.

    Article  CAS  Google Scholar 

  16. Meng, X. M., Nikolic-Paterson, D. J., & Lan, H. Y. (2016). TGF-beta: The master regulator of fibrosis. Nature Reviews Nephrology, 12, 325–338.

    Article  CAS  Google Scholar 

  17. Chen, J. T., Wang, C. Y., & Chen, M. H. (2018). Curcumin inhibits TGF-beta1-induced connective tissue growth factor expression through the interruption of Smad2 signaling in human gingival fibroblasts. Journal of the Formosan Medical Association, 117, 1115–1123.

    Article  CAS  Google Scholar 

  18. Yamamoto, T., Noble, N. A., Miller, D. E., Gold, L. I., Hishida, A., Nagase, M., Cohen, A. H., & Border, W. A. (1999). Increased levels of transforming growth factor-beta in HIV-associated nephropathy. Kidney International, 55, 579–592.

    Article  CAS  Google Scholar 

  19. Sawaya, B. E., Thatikunta, P., Denisova, L., Brady, J., Khalili, K., & Amini, S. (1998). Regulation of TNFalpha and TGFbeta-1 gene transcription by HIV-1 Tat in CNS cells. Journal of Neuroimmunology, 87, 33–42.

    Article  CAS  Google Scholar 

  20. Lotz, M., Clark-Lewis, I., & Ganu, V. (1994). HIV-1 transactivator protein Tat induces proliferation and TGF beta expression in human articular chondrocytes. Journal of Cell Biology, 124, 365–371.

    Article  CAS  Google Scholar 

  21. Barreto-de-Souza, V., Xavier Medeiros, T., Machado Motta, M. C., Bou-Habib, D. C., & Saraiva, E. M. (2008). HIV-1 infection and HIV-1 Tat protein permit the survival and replication of a non-pathogenic trypanosomatid in macrophages through TGF-beta1 production. Microbes and Infection, 10, 642–649.

    Article  CAS  Google Scholar 

  22. Chu, Q., Jiang, Y., Zhang, W., Xu, C., Du, W., Tuguzbaeva, G., Qin, Y., Li, A., Zhang, L., Sun, G., Cai, Y., Feng, Q., Li, G., Li, Y., Du, Z., Bai, Y., & Yang, B. (2016). Pyroptosis is involved in the pathogenesis of human hepatocellular carcinoma. Oncotarget, 7, 84658–84665.

    Article  Google Scholar 

  23. Jiang, Y., Du, W., Chu, Q., Qin, Y., Tuguzbaeva, G., Wang, H., Li, A., Li, G., Li, Y., Chai, L., Yue, E., Sun, X., Wang, Z., Pavlov, V., Yang, B., & Bai, Y. (2018). Downregulation of long non-coding RNA Kcnq1ot1: An important mechanism of arsenic trioxide-induced long QT syndrome. Cellular Physiology and Biochemistry, 45, 192–202.

    Article  CAS  Google Scholar 

  24. Gu, J., Babayeva, N. D., Suwa, Y., Baranovskiy, A. G., Price, D. H., & Tahirov, T. H. (2014). Crystal structure of HIV-1 Tat complexed with human P-TEFb and AFF4. Cell Cycle, 13, 1788–1797.

    Article  CAS  Google Scholar 

  25. Lapierre, J., Rodriguez, M., Ojha, C. R., & El-Hage, N. (2018). Critical role of Beclin1 in HIV Tat and morphine-induced inflammation and calcium release in glial cells from autophagy deficient mouse. Journal of Neuroimmune Pharmacology: The Official Journal of the Society on NeuroImmune Pharmacology, 13(3), 355–370.

    Article  Google Scholar 

  26. Tahrir, F. G., Shanmughapriya, S., Ahooyi, T. M., Knezevic, T., Gupta, M. K., Kontos, C. D., McClung, J. M., Madesh, M., Gordon, J., Feldman, A. M., Cheung, J. Y., & Khalili, K. (2018). Dysregulation of mitochondrial bioenergetics and quality control by HIV-1 Tat in cardiomyocytes. Journal of Cellular Physiology, 233, 748–758.

    Article  CAS  Google Scholar 

  27. Altavilla, G., Caputo, A., Trabanelli, C., Brocca Cofano, E., Sabbioni, S., Menegatti, M. A., Barbanti-Brodano, G., & Corallini, A. (2004). Prevalence of liver tumours in HIV-1 tat-transgenic mice treated with urethane. European Journal of Cancer, 40, 275–283.

    Article  CAS  Google Scholar 

  28. Hahn, Y. K., Podhaizer, E. M., Farris, S. P., Miles, M. F., Hauser, K. F., & Knapp, P. E. (2015). Effects of chronic HIV-1 Tat exposure in the CNS: Heightened vulnerability of males versus females to changes in cell numbers, synaptic integrity, and behavior. Brain Structure & Function, 220, 605–623.

    Article  Google Scholar 

  29. Chiozzini, C., & Toschi, E. (2016). HIV-1 TAT and immune dysregulation in aids pathogenesis: A therapeutic target. Current Drug Targets, 17, 33–45.

    Article  CAS  Google Scholar 

  30. Jiang, Y., Chai, L., Fasae, M. B., & Bai, Y. (2018). The role of HIV Tat protein in HIV-related cardiovascular diseases. Journal of Translational Medicine, 16, 121.

    Article  CAS  Google Scholar 

  31. Poggi, A., Carosio, R., Fenoglio, D., Brenci, S., Murdaca, G., Setti, M., Indiveri, F., Scabini, S., Ferrero, E., & Zocchi, M. R. (2004). Migration of V delta 1 and V delta 2 T cells in response to CXCR3 and CXCR4 ligands in healthy donors and HIV-1-infected patients: Competition by HIV-1 Tat. Blood, 103, 2205–2213.

    Article  CAS  Google Scholar 

  32. Badou, A., Bennasser, Y., Moreau, M., Leclerc, C., Benkirane, M., & Bahraoui, E. (2000). Tat protein of human immunodeficiency virus type 1 induces interleukin-10 in human peripheral blood monocytes: Implication of protein kinase C-dependent pathway. Journal of Virology, 74, 10551–10562.

    Article  CAS  Google Scholar 

  33. Goldstein, G., Manson, K., Tribbick, G., & Smith, R. (2000). Minimization of chronic plasma viremia in rhesus macaques immunized with synthetic HIV-1 Tat peptides and infected with a chimeric simian/human immunodeficiency virus (SHIV33). Vaccine, 18, 2789–2795.

    Article  CAS  Google Scholar 

  34. Zhou, D., Li, Z., Zhang, L., & Zhan, C. (2012). Inhibitory effect of tanshinone II A on TGF II-beta1-induced cardiac fibrosis. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban, 32, 829–833.

    Article  CAS  Google Scholar 

  35. Huang, Z. W., Tian, L. H., Yang, B., & Guo, R. M. (2017). Long noncoding RNA H19 acts as a competing endogenous RNA to mediate CTGF expression by sponging miR-455 in cardiac fibrosis. DNA and Cell Biology, 36, 759–766.

    Article  CAS  Google Scholar 

  36. Huang, J., Matavelli, L. C., & Siragy, H. M. (2011). Renal (pro)renin receptor contributes to development of diabetic kidney disease through transforming growth factor-beta1-connective tissue growth factor signalling cascade. Clinical and Experimental Pharmacology & Physiology, 38, 215–221.

    Article  CAS  Google Scholar 

  37. Dalvi, P., Sharma, H., Konstantinova, T., Sanderson, M., Brien-Ladner, A. O., & Dhillon, N. K. (2017). Hyperactive TGF-beta signaling in smooth muscle cells exposed to HIV-protein(s) and cocaine: Role in pulmonary vasculopathy. Scientific Reports, 7, 10433.

    Article  Google Scholar 

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Acknowledgements

The manuscript has been reviewed and accepted for publication in Cardiovascular Toxicology by all authors (Jiang YN, Chai L, Wang HG, Shen XY, Fasae MB, Jiao JF, Yu YH, Ju JM, Liu B, Bai YL). This work was supported by the National Natural Science Foundation of China (Grant No. 81673426, 81803524, 51708092, and 81803012), the China Postdoctoral Science Foundation (Grant No. 2018M641878), the Heilongjiang Postdoctoral Foundation (Grant No. LBH-Z18168), and the Foundation of Health Commission of Heilongjiang Province (Grant No. 2018484).

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Author notes

  1. Yannan Jiang and Lu Chai contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology (State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, People’s Republic of China

    Yannan Jiang, Lu Chai, Xiuyun Shen, Moyondafoluwa Blessing Fasae, Jinfeng Jiao, Yahan Yu, Jiaming Ju & Yunlong Bai

  2. Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, 150086, People’s Republic of China

    Yannan Jiang, Bing Liu & Yunlong Bai

  3. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, People’s Republic of China

    Yannan Jiang

  4. Department of Pharmacy, Inner Mongolia Cancer Hospital, Huhhot, 010000, People’s Republic of China

    Lu Chai

  5. School of Civil Engineering, Northeast Forestry University, Harbin, 150040, People’s Republic of China

    Hongguang Wang

  6. Key Laboratory of Bio-Based Material Science and Technology (Ministry of Education), School of Material Science and Engineering, Northeast Forestry University, Harbin, 150040, People’s Republic of China

    Hongguang Wang

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  1. Yannan Jiang
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Correspondence to Yunlong Bai.

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All the authors declare no competing financial interests.

Ethics Approval

All the animal experimental methods were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). And all experimental protocols were pre-approved by Institutional Review Board (IRB, No. 2019004) of College of Pharmacy, Harbin Medical University.

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Jiang, Y., Chai, L., Wang, H. et al. HIV Tat Protein Induces Myocardial Fibrosis Through TGF-β1-CTGF Signaling Cascade: A Potential Mechanism of HIV Infection-Related Cardiac Manifestations. Cardiovasc Toxicol 21, 965–972 (2021). https://doi.org/10.1007/s12012-021-09687-6

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