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ALK1 Deficiency Impairs the Wound-Healing Process and Increases Mortality in Murine Model of Myocardial Infarction

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Abstract

The functional role of TGFβ type I receptor, activin-like kinase (ALK)-1 in post-myocardial infarction (MI) cardiac remodeling is unknown. We hypothesize that reduced ALK1 activity reduces survival and promotes cardiac fibrosis after MI. MI was induced in wild-type (WT), and ALK+/− mice by left coronary ligation. After 14 days ALK1+/− mice had reduced survival with a higher rate of cardiac rupture compared to WT mice. ALK1+/− left ventricles (LVs) had increased volumes at the end of systole and at the end of diastole. After MI ALK1+/− LVs had increased profibrotic SMAD3 signaling, type 1 collagen, and fibrosis as well as increased levels of TGFβ1 co-receptor, endoglin, VEGF, and ALK1 ligands BMP9 and BMP10. ALK1+/− LVs had decreased levels of stromal-derived factor 1α. These data identify the critical role of ALK1 in post-MI survival and cardiac remodeling and implicate ALK1 as a potential therapeutic target to improve survival after MI.

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Abbreviations

MI:

Myocardial infarction

TGFβ:

Transforming growth factor beta

ALK1:

Activin-like kinase 1

BMP:

Bone morphogenetic protein

LCA:

Left coronary artery

α-SMA:

α-smooth muscle actin

References

  1. Kannel WB, Sorlie P, McNamara PM. Prognosis after initial myocardial infarction: the Framingham study. Am J Cardiol. 1979;44:53–9.

    Article  CAS  PubMed  Google Scholar 

  2. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation. 2020;141:e139–596.

    Article  PubMed  Google Scholar 

  3. Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction—from repair and remodeling to regeneration. Cell Tissue Res. 2016;365:563–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ertl G, Frantz S. Healing after myocardial infarction. Cardiovasc Res. 2005;66:22–32.

    Article  CAS  PubMed  Google Scholar 

  5. Frantz S, Hundertmark MJ, Schulz-Menger J, Bengel FM, Bauersachs J. Left ventricular remodelling post-myocardial infarction: pathophysiology, imaging, and novel therapies. Eur Heart J. 2022;43(27):2549–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bujak M, Frangogiannis NG. The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. CardiovascRes. 2007;74:184–95.

    Article  CAS  Google Scholar 

  7. Bujak M, Ren G, Kweon HJ, et al. Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling. Circulation. 2007;116:2127–38.

    Article  CAS  PubMed  Google Scholar 

  8. Matsui Y, Morimoto J, Uede T. Role of matricellular proteins in cardiac tissue remodeling after myocardial infarction. World J Biol Chem. 2010;1:69–80.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lamouille S, Mallet C, Feige J-J, et al. Activin receptor–like kinase 1 is implicated in the maturation phase of angiogenesis. Blood. 2002;100:4495–501.

    Article  CAS  PubMed  Google Scholar 

  10. Oh SP, Seki T, Goss KA, et al. Activin receptor-like kinase 1 modulates transforming growth factor-β1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A. 2000;97:2626–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996;13:189–95.

    Article  CAS  PubMed  Google Scholar 

  12. Leask A. Getting to the heart of the matter. Circ Res. 2015;116:1269–76.

    Article  CAS  PubMed  Google Scholar 

  13. Morine KJ, Qiao X, Paruchuri V, et al. Reduced activin receptor-like kinase 1 activity promotes cardiac fibrosis in heart failure. CardiovascPathol. 2017;31:26–33.

    CAS  Google Scholar 

  14. Morine KJ, Qiao X, York S, et al. Bone morphogenetic protein 9 reduces cardiac fibrosis and improves cardiac function in heart failure. Circulation. 2018;138:513–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fernández B, Durán AC, Fernández MC, et al. The coronary arteries of the C57BL/6 mouse strains: implications for comparison with mutant models. J Anat. 2008;212:12–8.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Scalise RFM, De Sarro R, Caracciolo A, et al. Fibrosis after myocardial infarction: an overview on cellular processes, molecular pathways, clinical evaluation and prognostic value. Med Sci. 2021;9:16.

    CAS  Google Scholar 

  17. Bhave S, Esposito M, Swain L, et al. Loss of bone morphogenetic protein-9 reduces survival and increases MMP activity after myocardial infarction. JACC Basic Transl Sci. 2023;8:1318–30.

    Article  Google Scholar 

  18. Sullivan KE, Quinn KP, Tang KM, et al. Extracellular matrix remodeling following myocardial infarction influences the therapeutic potential of mesenchymal stem cells. Stem Cell Res Ther. 2014;5:14.

    Article  PubMed  PubMed Central  Google Scholar 

  19. David L, Mallet C, Mazerbourg S, et al. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood. 2007;109:1953–61.

    Article  CAS  PubMed  Google Scholar 

  20. Scharpfenecker M, Floot B, Russell NS, et al. The TGF-Î2 co-receptor endoglin regulates macrophage infiltration and cytokine production in the irradiated mouse kidney. RadiotherOncol. 2012;105:313–20.

    CAS  Google Scholar 

  21. Wu X, Reboll MR, Korf-Klingebiel M, et al. Angiogenesis after acute myocardial infarction. Cardiovasc Res. 2021;117:1257–73.

    Article  CAS  PubMed  Google Scholar 

  22. Sánchez-Elsner T, Botella LM, Velasco B, et al. Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-β pathways*. J Biol Chem. 2002;277:43799–808.

    Article  PubMed  Google Scholar 

  23. Shao ES, Lin L, Yao Y, et al. Expression of vascular endothelial growth factor is coordinately regulated by the activin-like kinase receptors 1 and 5 in endothelial cells. Blood. 2009;114:2197–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. McDonald J, Bayrak-Toydemir P, DeMille D, et al. Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2). Genet Med. 2020;22:1201–5.

    Article  CAS  PubMed  Google Scholar 

  25. Hu X, Dai S, Wu W-J, et al. Stromal cell–derived factor-1α confers protection against myocardial ischemia/reperfusion injury. Circulation. 2007;116:654–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Saxena A, Fish JE, White MD, et al. Stromal cell-derived factor-1alpha is cardioprotective after myocardial infarction. Circulation. 2008;117:2224–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hiasa K, Ishibashi M, Ohtani K, et al. Gene transfer of stromal cell-derived factor-1alpha enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: next-generation chemokine therapy for therapeutic neovascularization. Circulation. 2004;109:2454–61.

    Article  CAS  PubMed  Google Scholar 

  28. Yamaguchi J, Kusano KF, Masuo O, et al. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation. 2003;107:1322–8.

    Article  CAS  PubMed  Google Scholar 

  29. Young K, Conley B, Romero D, et al. BMP9 regulates endoglin-dependent chemokine responses in endothelial cells. Blood. 2012;120:4263–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was funded by the National Institute of Health grants R01HL133215 (NKK) and R01HL139785 (NKK).

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Authors and Affiliations

  1. Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, 02111, USA

    Shreyas Bhave, Lija Swain, Xiaoying Qiao, Gregory Martin, Tejasvi Aryaputra, Kay Everett & Navin K. Kapur

Authors
  1. Shreyas Bhave
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  2. Lija Swain
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  3. Xiaoying Qiao
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  4. Gregory Martin
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  5. Tejasvi Aryaputra
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  6. Kay Everett
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  7. Navin K. Kapur
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Corresponding author

Correspondence to Navin K. Kapur.

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Competing Interests

Dr. Kapur receives institutional grant support and speaker/consulting honoraria from Abbott, Abiomed, Boston Scientific, LivaNova, Medtronic, MD Start, and Precardia.

Human and Animal Rights and Informed Consent

No human studies were carried out for the generation of data in this article.

Clinical Relevance

Post myocardial infarction wound healing process is crucial for the patient’s survival as well as the development of heart disease. The ALK1/BMP9 pathway is an emerging target for the development of novel therapies for both cancers and cardiovascular diseases. Data presented here sheds more light on the role of this pathway in the cardiac wound healing process thus identifying unique molecular targets for future treatments.

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Associate Editor Joost Sluijter oversaw the review of this article

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Bhave, S., Swain, L., Qiao, X. et al. ALK1 Deficiency Impairs the Wound-Healing Process and Increases Mortality in Murine Model of Myocardial Infarction. J. of Cardiovasc. Trans. Res. (2023). https://doi.org/10.1007/s12265-023-10471-w

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