Emerging Molecular Pathways Involved in Pathophysiology of Cardiac Remodeling
Mammalian heart is a dynamic organ that can adapt morphological changes in response to alteration in workload. Various clinical and experimental findings revealed that in response to physiological stimuli or pathological insults, the heart undergoes cardiac remodeling which can be characterized by molecular, cellular or interstitial changes and can be manifested clinically as changes in size, shape and pumping function of the heart. A Sound understanding of changes in hearts cellular and molecular components and to mediators that derive homeostatic control is necessary before a specific intervention is pursued. Summarized data of this review comprises role of various novel emerging molecular pathways involvement in the pathophysiology of cardiac remodeling.
Keywords: Cardiac remodeling, hypertrophy, protein kinase, heart failure, molecular targets, pathological insult.
2. Redon J, Cifkova R, Laurent S, Nilsson P, Narkiewicz K, Erdine S, et al. Mechanisms of hypertension in the cardiometabolic syndrome. Journal of hypertension. 2009; 27(3):441-51.
3. Nakayama M, Ishidoh K, Kayagaki N, Kojima Y, Yamaguchi N, Nakano H, et al. Multiple pathways of TWEAK-induced cell death. The Journal of Immunology. 2002; 168(2):734-43.
4. Brown SA, Hanscom HN, Vu H, Brew SA, Winkles JA. TWEAK binding to the Fn14 cysteine-rich domain depends on charged residues located in both the A1 and D2 modules. Biochemical Journal. 2006; 397(2):297-304.
5. Novoyatleva T, Diehl F, Van Amerongen MJ, Patra C, Ferrazzi F, Bellazzi R, et al. TWEAK is a positive regulator of cardiomyocyte proliferation. Cardiovascular research. 2010; 85(4):681-90.
6. Mustonen E, Säkkinen H, Tokola H, Isopoussu E, Aro J, Leskinen H, et al. Tumour necrosis factor‐like weak inducer of apoptosis (TWEAK) and its receptor Fn14 during cardiac remodelling in rats. Acta Physiologica. 2010; 199(1):11-22.
7. Bian Z, Dai J, Hiroyasu N, Guan H, Yuan Y, Gan L, et al. Disruption of tumor necrosis factor receptor associated factor 5 exacerbates pressure overload cardiac hypertrophy and fibrosis. Journal of Cellular Biochemistry. 2014; 115(2):349-58.
8. Qi X, Li Z, Li H, Wang T, Zhang Y, Wang J. MicroRNA-1 Negatively Regulates Peripheral NK Cell Function via Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Signaling Pathways During PPRV Infection. Frontiers in Immunology. 2020; 10:3066.
9. Novoyatleva T, Sajjad A, Engel FB. TWEAK-Fn14 cytokine-receptor axis: a new player of myocardial remodeling and cardiac failure. Frontiers in immunology. 2014; 5:50.
10. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochemical and biophysical research communications. 1997; 236(2):313-22.
11. Afanas' ev I. ROS and RNS signaling in heart disorders: could antioxidant treatment be successful? Oxidative medicine and cellular longevity. 2011; 2011.
12. Li J, Ichikawa T, Villacorta L, Janicki JS, Brower GL, Yamamoto M, et al. Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arteriosclerosis, thrombosis, and vascular biology. 2009; 29(11):1843-50.
13. Gupta S, Das B, Sen S. Cardiac hypertrophy: mechanisms and therapeutic opportunities. Antioxidants & redox signaling. 2007; 9(6):623-52.
14. Zeng Z, Wang Z-y, Li Y-k, Ye D-m, Zeng J, Hu J-l, et al. Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) in non-small cell lung cancer. Life Sciences. 2020; 254:117325.
15. Ichihara S, Yamada Y, Kawai Y, Osawa T, Furuhashi K, Duan Z, et al. Roles of oxidative stress and Akt signaling in doxorubicin cardiotoxicity. Biochemical and biophysical research communications. 2007; 359(1):27-33.
16. Ono K, Han J. The p38 signal transduction pathway activation and function. Cellular signalling. 2000; 12(1):1-13.
17. Turner NA, Blythe NM. Cardiac fibroblast p38 MAPK: a critical regulator of myocardial remodeling. Journal of cardiovascular development and disease. 2019; 6(3):27.
18. Huang C, Ma W-Y, Maxiner A, Sun Y, Dong Z. p38 kinase mediates UV-induced phosphorylation of p53 protein at serine 389. Journal of Biological Chemistry. 1999;274(18):12229-35.
19. Barger PM, Browning AC, Garner AN, Kelly DP. p38 Mitogen-activated protein kinase activates peroxisome proliferator-activated receptor α a potential role in the cardiac metabolic stress response. Journal of Biological Chemistry. 2001; 276(48):44495-501.
20. Isgaard J. Ghrelin and the cardiovascular system. The Ghrelin System. 25: Karger Publishers; 2013. p. 83-90.
21. Iglesias MJ, Piñeiro R, Blanco M, Gallego R, Diéguez C, Gualillo O, et al. Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes. Cardiovascular research. 2004; 62(3):481-8.
22. Holliday ND, Holst B, Rodionova EA, Schwartz TW, Cox HM. Importance of constitutive activity and arrestin-independent mechanisms for intracellular trafficking of the ghrelin receptor. Molecular endocrinology. 2007; 21(12):3100-12.
23. Iantorno M, Chen H, Kim J-a, Tesauro M, Lauro D, Cardillo C, et al. Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells. American Journal of Physiology-Endocrinology and Metabolism. 2007; 292(3):E756-E64.
24. Yuan M-J, Wang T, Kong B, Wang X, Huang C-X, Wang D. GHSR-1a is a novel pro-angiogenic and anti-remodeling target in rats after myocardial infarction. European journal of pharmacology. 2016; 788:218-25.
25. Beiras-Fernandez A, Kreth S, Weis F, Ledderose C, Pöttinger T, Dieguez C, et al. Altered myocardial expression of ghrelin and its receptor (GHSR-1a) in patients with severe heart failure. Peptides. 2010; 31(12):2222-8.
26. Casteel DE, Smith-Nguyen EV, Sankaran B, Roh SH, Pilz RB, Kim C. A crystal structure of the cyclic GMP-dependent protein kinase Iβ dimerization/docking domain reveals molecular details of isoform-specific anchoring. Journal of Biological Chemistry. 2010; 285(43):32684-8.
27. Kishimoto I, Rossi K, Garbers DL. A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy. Proceedings of the National Academy of Sciences. 2001; 98(5):2703-6.
28. Yang L, Liu G, Zakharov SI, Bellinger AM, Mongillo M, Marx SO. Protein kinase G phosphorylates Cav1. 2 α1c and β2 subunits. Circulation research. 2007; 101(5):465-74.
29. Suetomi T, Willeford A, Brand CS, Cho Y, Ross RS, Miyamoto S, et al. Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by Ca2+/calmodulin-dependent protein kinase II δ signaling in cardiomyocytes are essential for adverse cardiac remodeling. Circulation. 2018; 138(22):2530-44.
30. Sawada N, Itoh H, Miyashita K, Tsujimoto H, Sone M, Yamahara K, et al. Cyclic GMP kinase and RhoA Ser188 phosphorylation integrate pro-and antifibrotic signals in blood vessels. Molecular and cellular biology. 2009; 29(22):6018-32.
31. Fiedler B, Feil R, Hofmann F, Willenbockel C, Drexler H, Smolenski A, et al. cGMP-dependent protein kinase type I inhibits TAB1-p38 mitogen-activated protein kinase apoptosis signaling in cardiac myocytes. Journal of Biological Chemistry. 2006; 281(43):32831-40.
32. Marx N, Duez H, Fruchart J-C, Staels B. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circulation research. 2004; 94(9):1168-78.
33. Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S. The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases. Journal of advanced pharmaceutical technology & research. 2011; 2(4):236.
34. Lu Q, Guo P, Guo J, Ares I, Lopez-Torres B, Martínez-Larrañaga M-R, et al. Targeting peroxisome proliferator-activated receptors: A new strategy for the treatment of cardiac fibrosis. Pharmacology & Therapeutics. 2020:107702.
35. Azhar S. Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease. Future cardiology. 2010; 6(5):657-91.
36. Barger PM, Brandt JM, Leone TC, Weinheimer CJ, Kelly DP. Deactivation of peroxisome proliferator–activated receptor-α during cardiac hypertrophic growth. The Journal of clinical investigation. 2000; 105(12):1723-30.
37. Maruyama S, Kato K, Kodama M, Hirono S, Fuse K, Nakagawa O, et al. Fenofibrate, a peroxisome proliferator-activated receptor α activator, suppresses experimental autoimmune myocarditis by stimulating the interleukin-10 pathway in rats. Journal of atherosclerosis and thrombosis. 2002; 9(2):87-92.
38. Diep QN, Benkirane K, Amiri F, Cohn JS, Endemann D, Schiffrin EL. PPARα activator fenofibrate inhibits myocardial inflammation and fibrosis in angiotensin II-infused rats. Journal of molecular and cellular cardiology. 2004; 36(2):295-304.
39. Wang C-H, Weisel RD, Liu PP, Fedak PW, Verma S. Glitazones and heart failure: critical appraisal for the clinician. Circulation. 2003; 107(10):1350-4.
40. Schiffrin EL. Peroxisome proliferator-activated receptors and cardiovascular remodeling. American Journal of Physiology-Heart and Circulatory Physiology. 2005; 288(3):H1037-H43.
41. Disatnik M-H, Buraggi G, Mochly-Rosen D. Localization of Protein Kinase C Isozymes in Cardiac Myocytes. Experimental Cell Research. 1994; 210(2):287-97.
42. Ferreira JCB, Koyanagi T, Palaniyandi SS, Fajardo G, Churchill EN, Budas G, et al. Pharmacological inhibition of βIIPKC is cardioprotective in late-stage hypertrophy. Journal of Molecular and Cellular Cardiology. 2011; 51(6):980-7.
43. Palaniyandi SS, Inagaki K, Mochly-Rosen D. Mast cells and ɛPKC: A role in cardiac remodeling in hypertension-induced heart failure. Journal of Molecular and Cellular Cardiology. 2008; 45(6):779-86.
44. Xie Z, Singh M, Singh K. Differential regulation of matrix metalloproteinase-2 and-9 expression and activity in adult rat cardiac fibroblasts in response to interleukin-1β. Journal of Biological Chemistry. 2004; 279(38):39513-9.
45. Lim J-Y, Park SJ, Hwang H-Y, Park EJ, Nam JH, Kim J, et al. TGF-β1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation. Journal of molecular and cellular cardiology. 2005; 39(4):627-36.
46. Wu G, Wang Z, Shan P, Huang S, Lin S, Huang W, et al. Suppression of Netrin-1 attenuates angiotension II-induced cardiac remodeling through the PKC/MAPK signaling pathway. Biomedicine & Pharmacotherapy. 2020; 130:110495.
47. Takeishi Y, Chu G, Kirkpatrick DM, Li Z, Wakasaki H, Kranias EG, et al. In Vivo Phosphorylation of Cardiac Troponin I by Protein Kinase C [small beta, Greek] 2 Decreases Cardiomyocyte Calcium Responsiveness and Contractility in Transgenic Mouse Hearts. The Journal of Clinical Investigation. 1998; 102(1):72-8.
48. Herceg Z, Wang Z-Q. Functions of poly (ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2001; 477(1-2):97-110.
49. Schreiber V, Dantzer F, Ame J-C, De Murcia G. Poly (ADP-ribose): novel functions for an old molecule. Nature reviews Molecular cell biology. 2006; 7(7):517-28.
50. Henning RJ, Bourgeois M, Harbison RD. Poly (ADP-ribose) polymerase (PARP) and PARP inhibitors: mechanisms of action and role in cardiovascular disorders. Cardiovascular toxicology. 2018; 18(6):493-506.
51. Hassa PO, Haenni SS, Buerki C, Meier NI, Lane WS, Owen H, et al. Acetylation of poly (ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-κB-dependent transcription. Journal of biological chemistry. 2005; 280(49):40450-64.
52. Pacher P, Schulz R, Liaudet L, Szabó C. Nitrosative stress and pharmacological modulation of heart failure. Trends in Pharmacological Sciences. 2005; 26(6):302-10.
53. Budzyn K, Marley PD, Sobey CG. Targeting Rho and Rho-kinase in the treatment of cardiovascular disease. Trends in pharmacological sciences. 2006; 27(2):97-104.
54. Jalil J, Lavandero S, Chiong M, Ocaranza MP. Rho/Rho kinase signal transduction pathway in cardiovascular disease and cardiovascular remodeling. Revista Española de Cardiología (English Edition). 2005; 58(8):951-61.
55. Elrashidy RA, Zhang J, Liu G. Long-term consumption of Western diet contributes to endothelial dysfunction and aortic remodeling in rats: Implication of Rho-kinase signaling. Clinical and Experimental Hypertension. 2019; 41(2):174-80.
56. Kobayashi N, Horinaka S, Mita S-i, Nakano S, Honda T, Yoshida K, et al. Critical role of Rho-kinase pathway for cardiac performance and remodeling in failing rat hearts. Cardiovascular research. 2002; 55(4):757-67.
57. Hla T, Maciag T. An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors. Journal of Biological Chemistry. 1990; 265(16):9308-13.
58. Cannavo A, Liccardo D, Komici K, Corbi G, de Lucia C, Femminella GD, et al. Sphingosine kinases and sphingosine 1-phosphate receptors: signaling and actions in the cardiovascular system. Frontiers in pharmacology. 2017; 8:556.
59. Pyne S, Pyne NJ. Sphingosine 1-phosphate signalling in mammalian cells. Biochemical Journal. 2000; 349(2):385-402.
60. Kon J, Sato K, Watanabe T, Tomura H, Kuwabara A, Kimura T, et al. Comparison of intrinsic activities of the putative sphingosine 1-phosphate receptor subtypes to regulate several signaling pathways in their cDNA-transfected Chinese hamster ovary cells. Journal of Biological Chemistry. 1999; 274(34):23940-7.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).