TLR-Dependent Pathways and Akt/mTOR/P70S6K Pathways in Cardiac Remodeling After Myocardial Infarction

Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 5)


Left ventricular remodeling is a progressive process which starts immediately after acute myocardial infarction (MI) and evolves in the chronic phase of heart failure. The molecular and cellular changes associated with ventricular remodeling affect both the cardiomyocytes and the interstitial space and manifest clinically as increased ventricular size, altered shape of the ventricle, and worsened cardiac function. Specific therapy to optimize healing and prevent adverse post-MI remodeling is currently lacking. Understanding of the specific events (time and space) that occur in response to MI and are involved in infarct healing is crucial to abrogate postinfarction ventricular remodeling and/or stimulate the healing process. Inflammation and extracellular matrix remodeling are two key components associated with LV remodeling after MI. Myocardial injury upon MI activates an inflammatory response that orchestrates the cardiac repair process through a complex cascade involving cytokines, other inflammatory mediators, and growth factors. In this regard, the innate immune system, such as that mediated by the Toll-like receptors (TLRs), has appeared during the past decade as a major contributor to the pathogenesis of MI by modulating cell survival and tissue injury. Cardiac remodeling also encompasses many changes in the myocardial interstitium leading to fibrosis and hypertrophy. The mammalian target of rapamycin (mTOR) signaling has shown to exert a broad spectrum of functions including cell cycle progression, hypertrophy, protein synthesis, autophagy, and angiogenesis, all of which largely contribute to the fibrotic reparative scar.

This chapter aims to provide an in-depth analysis of the contribution of both the innate immune system (via TLR activation) and the activation of Akt/mTOR/P70S6K in the cardiac remodeling phase post-MI.


Myocardial infarction Cardiac remodeling Inflammation Innate immune system Toll-like receptor mTOR Hypertrophy Autophagy Fibrosis Matrix remodeling 



High-mobility group box




Interferon-regulatory factor-3


Left ventricle


Myocardial infarction


Mammalian target of rapamycin


Myeloid differentiation factor 88


Nuclear factor kappa-light-chain-enhancer of activated B cells


Phosphoinositide 3-kinase


Toll-like receptors


Tumor necrosis factor


mTOR complex


Tumor necrosis factor receptor-associated factor-6


TRIF-related adaptor molecule


TIR domain-containing adaptor protein inducing type 1 interferons


Vascular endothelial growth factor


Wild type


  1. 1.
    Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820PubMedCrossRefGoogle Scholar
  2. 2.
    Anderson KV, Bokla L, Nusslein-Volhard C (1985) Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell 42:791–798PubMedCrossRefGoogle Scholar
  3. 3.
    Arumugam TV, Okun E, Tang SC et al (2009) Toll-like receptors in ischemia-reperfusion injury. Shock 32:4–16PubMedCrossRefGoogle Scholar
  4. 4.
    Wang Y, Abarbanell AM, Herrmann JL et al (2010) Toll-like receptor signaling pathways and the evidence linking toll-like receptor signaling to cardiac ischemia/reperfusion injury. Shock 34:548–557PubMedCrossRefGoogle Scholar
  5. 5.
    Chao W (2009) Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart. Am J Physiol Heart Circ Physiol 296:H1–H12PubMedCrossRefGoogle Scholar
  6. 6.
    Scheibner KA, Lutz MA, Boodoo S et al (2006) Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol 177:1272–1281PubMedGoogle Scholar
  7. 7.
    Okamura Y, Watari M, Jerud ES et al (2001) The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem 276:10229–10233PubMedCrossRefGoogle Scholar
  8. 8.
    Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195PubMedCrossRefGoogle Scholar
  9. 9.
    Su X, Sykes JB, Ao L et al (2010) Extracellular heat shock cognate protein 70 induces cardiac functional tolerance to endotoxin: differential effect on TNF-alpha and ICAM-1 levels in heart tissue. Cytokine 51:60–66PubMedCrossRefGoogle Scholar
  10. 10.
    Frantz SEG, Bauersachs J (2007) Mechanisms of disease Toll-like receptors in cardiovasculardisease. Nat Clin Pract Cardiovasc Med 4:444–454PubMedCrossRefGoogle Scholar
  11. 11.
    Aikawa R, Nagai T, Tanaka M et al (2001) Reactive oxygen species in mechanical stress-induced cardiac hypertrophy. Biochem Biophys Res Commun 289:901–907PubMedCrossRefGoogle Scholar
  12. 12.
    Bolli R, Marban E (1999) Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 79:609–634PubMedGoogle Scholar
  13. 13.
    Vilahur G, Hernandez-Vera R, Molins B et al (2009) Short-term myocardial ischemia induces cardiac modified C-reactive protein expression and proinflammatory gene (cyclooxygenase-2, monocyte chemoattractant protein-1, and tissue factor) upregulation in peripheral blood mononuclear cells. J Thromb Haemost 7:485–493PubMedCrossRefGoogle Scholar
  14. 14.
    Vilahur G, Juan-Babot O, Pena E et al (2011) Molecular and cellular mechanisms involved in cardiac remodeling after acute myocardial infarction. J Mol Cell Cardiol 50(3):522–533PubMedCrossRefGoogle Scholar
  15. 15.
    Chong AJ, Shimamoto A, Hampton CR et al (2004) Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart. J Thorac Cardiovasc Surg 128:170–179PubMedCrossRefGoogle Scholar
  16. 16.
    Oyama J, Blais C Jr, Liu X et al (2004) Reduced myocardial ischemia-reperfusion injury in toll- like receptor 4-deficient mice. Circulation 109:784–789PubMedCrossRefGoogle Scholar
  17. 17.
    Sakata Y, Dong JW, Vallejo JG et al (2007) Toll-like receptor 2 modulates left ventricular function following ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 292:H503–H509PubMedCrossRefGoogle Scholar
  18. 18.
    Kim HM, Park BS, Kim JI et al (2007) Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell 130:906–917PubMedCrossRefGoogle Scholar
  19. 19.
    Hua F, Ha T, Ma J et al (2005) Blocking the MyD88-dependent pathway protects the myocardium from ischemia/reperfusion injury in rat hearts. Biochem Biophys Res Commun 338:1118–1125PubMedCrossRefGoogle Scholar
  20. 20.
    Sawa Y, Morishita R, Suzuki K et al (1997) A novel strategy for myocardial protection using in vivo transfection of cis element ‘decoy’ against NF-kappa B binding site: evidence for a role of NF-kappa B in ischemia-reperfusion injury. Circulation 96: II:280–284, discussion II-285Google Scholar
  21. 21.
    Brown M, McGuinness M, Wright T et al (2005) Cardiac-specific blockade of NF-kappa B in cardiac pathophysiology: differences between acute and chronic stimuli in vivo. Am J Physiol Heart Circ Physiol 289:H466–H476PubMedCrossRefGoogle Scholar
  22. 22.
    Onai Y, Suzuki J, Kakuta T, Maejima Y et al (2004) Inhibition of I-kappa B phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury. Cardiovasc Res 63:51–59PubMedCrossRefGoogle Scholar
  23. 23.
    Zhu X, Zhao H, Graveline AR et al (2006) MyD88 and NOS2 are essential for toll-like receptor 4-mediated survival effect in cardiomyocytes. Am J Physiol Heart Circ Physiol 291:H1900–H1909PubMedCrossRefGoogle Scholar
  24. 24.
    Balistreri CR, Candore G, Colonna-Romano G et al (2004) Role of Toll-like receptor 4 in acute myocardial infarction and longevity. JAMA 292:2339–2340PubMedCrossRefGoogle Scholar
  25. 25.
    Boekholdt SM, Agema WR, Peters RJ et al (2003) Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events. Circulation 107:2416–2421PubMedCrossRefGoogle Scholar
  26. 26.
    Edfeldt K, Bennet AM, Eriksson P et al (2004) Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction. Eur Heart J 25:1447–1453PubMedCrossRefGoogle Scholar
  27. 27.
    Koch W, Hoppmann P, Pfeufer A, Schomig A, Kastrati A (2006) Toll-like receptor 4 gene polymorphisms and myocardial infarction: no association in a Caucasian population. Eur Heart J 27:2524–2529PubMedCrossRefGoogle Scholar
  28. 28.
    Jugdutt BI (2003) Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? Circulation 108:1395–1403PubMedCrossRefGoogle Scholar
  29. 29.
    Nian M, Lee P, Khaper N, Liu P (2004) Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 94:1543–1553PubMedCrossRefGoogle Scholar
  30. 30.
    Morishita S, Kinoshita T (2008) Predictors of response to sertraline in patients with major depression. Hum Psychopharmacol 23:647–651PubMedCrossRefGoogle Scholar
  31. 31.
    Frantz S, Kobzik L, Kim YD et al (1999) Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest 104:271–280PubMedCrossRefGoogle Scholar
  32. 32.
    Birks EJ, Felkin LE, Banner NR et al (2004) Increased toll-like receptor 4 in the myocardium of patients requiring left ventricular assist devices. J Heart Lung Transplant 23:228–235PubMedCrossRefGoogle Scholar
  33. 33.
    Riad A, Jager S, Sobirey M et al (2008) Toll-like receptor-4 modulates survival by induction of left ventricular remodeling after myocardial infarction in mice. J Immunol 180:6954–6961PubMedGoogle Scholar
  34. 34.
    Van Tassell BW, Seropian IM, Toldo S et al (2010) Pharmacologic inhibition of myeloid differentiation factor 88 (MyD88) prevents left ventricular dilation and hypertrophy after experimental acute myocardial infarction in the mouse. J Cardiovasc Pharmacol 55:385–390PubMedCrossRefGoogle Scholar
  35. 35.
    Timmers L, van Keulen JK, Hoefer IE et al (2009) Targeted deletion of nuclear factor kappa B p50 enhances cardiac remodeling and dysfunction following myocardial infarction. Circ Res 104:699–706PubMedCrossRefGoogle Scholar
  36. 36.
    Frantz S, Hu K, Bayer B et al (2006) Absence of NF-kappa B subunit p50 improves heart failure after myocardial infarction. FASEB J 20:1918–1920PubMedCrossRefGoogle Scholar
  37. 37.
    Shishido T, Nozaki N, Yamaguchi S et al (2003) Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation 108:2905–2910PubMedCrossRefGoogle Scholar
  38. 38.
    Mersmann J, Habeck K, Latsch K et al (2011) Left ventricular dilation in toll-like receptor 2 deficient mice after myocardial ischemia/reperfusion through defective scar formation. Basic Res Cardiol 106:89–98PubMedCrossRefGoogle Scholar
  39. 39.
    Jugdutt BI (1998) Effect of nitroglycerin and ibuprofen on left ventricular topography and rupture threshold during healing after myocardial infarction in the dog. Can J Physiol Pharmacol 66:385–395CrossRefGoogle Scholar
  40. 40.
    Crackower MA, Oudit GY, Kozieradzki I et al (2002) Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110:737–749PubMedCrossRefGoogle Scholar
  41. 41.
    Guertin DA, Sabatini DM (2005) An expanding role for mTOR in cancer. Trends Mol Med 11:353–361PubMedCrossRefGoogle Scholar
  42. 42.
    Song X, Kusakari Y, Xiao CY et al (2010) mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy. Am J Physiol Cell Physiol 299:C1256–C1266PubMedCrossRefGoogle Scholar
  43. 43.
    Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:13375–13378PubMedCrossRefGoogle Scholar
  44. 44.
    Averous J, Proud CG (2006) When translation meets transformation: the mTOR story. Oncogene 25:6423–6435PubMedCrossRefGoogle Scholar
  45. 45.
    Buss SJ, Muenz S, Riffel JH et al (2009) Beneficial effects of Mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction. J Am Coll Cardiol 54:2435–2446PubMedCrossRefGoogle Scholar
  46. 46.
    Lajoie C, El-Helou V, Proulx C et al (2009) Infarct size is increased in female post-MI rats treated with rapamycin. Can J Physiol Pharmacol 87:460–470PubMedCrossRefGoogle Scholar
  47. 47.
    McMullen JR, Sherwood MC, Tarnavski O et al (2004) Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109:3050–3055PubMedCrossRefGoogle Scholar
  48. 48.
    Buss SJ, Riffel JH, Katus HA, Hardt SE (2010) Augmentation of autophagy by mTOR-inhibition in myocardial infarction: when size matters. Autophagy 6:304–306PubMedCrossRefGoogle Scholar
  49. 49.
    Hudson CC, Liu M, Chiang GG et al (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004–7014PubMedCrossRefGoogle Scholar
  50. 50.
    Shiojima I, Sato K, Izumiya Y et al (2005) Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115:2108–2118PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant PauBarcelonaSpain
  2. 2.CIBEROBN-Pathophysiology of Obesity and NutritionBarcelonaSpain
  3. 3.UABBarcelonaSpain

Personalised recommendations