A Small Peptide Ac-SDKP Inhibits Radiation-Induced Cardiomyopathy

Umesh C. Sharma, Swati D. Sonkawade, Joseph A. Spernyak, Sandra Sexton, Juliane Nguyen, Suraj Dahal, Kristopher M. Attwood, Anurag K. Singh, Jop van Berlo, Saraswati Pokharel

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Advances in radiotherapy for thoracic cancers have resulted in improvement of survival. However, radiation exposure to the heart can induce cardiotoxicity. No therapy is currently available to inhibit these untoward effects. We examined whether a small tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), can counteract radiation-induced cardiotoxicity by inhibiting macrophage-dependent inflammatory and fibrotic pathways. METHODS AND RESULTS: After characterizing a rat model of cardiac irradiation with magnetic resonance imaging protocols, we examined the effects of Ac-SDKP in radiation-induced cardiomyopathy. We treated rats with Ac-SDKP for 18 weeks. We then compared myocardial contractile function and extracellular matrix by cardiac magnetic resonance imaging and the extent of inflammation, fibrosis, and Mac-2 (galectin-3) release by tissue analyses. Because Mac-2 is a crucial macrophage-derived mediator of fibrosis, we performed studies to determine Mac-2 synthesis by macrophages in response to radiation, and change in profibrotic responses by Mac-2 gene depleted cardiac fibroblasts after radiation. Cardiac irradiation diminished myocardial contractile velocities and enhanced extracellular matrix deposition. This was accompanied by macrophage infiltration, fibrosis, cardiomyocyte apoptosis, and cardiac Mac-2 expression. Ac-SDKP strongly inhibited these detrimental effects. Ac-SDKP migrated into the perinuclear cytoplasm of the macrophages and inhibited radiation-induced Mac-2 release. Cardiac fibroblasts lacking the Mac-2 gene showed reduced transforming growth factor β1, collagen I, and collagen III expression after radiation exposure. CONCLUSIONS: Our study identifies novel cardioprotective effects of Ac-SDKP in a model of cardiac irradiation. These protective effects are exerted by inhibiting inflammation, fibrosis, and reducing macrophage activation. This study shows a therapeutic potential of this endogenously released peptide to counteract radiation-induced cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)e004867
JournalCirculation. Heart failure
Volume11
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

Cardiomyopathies
Radiation
Peptides
Macrophages
Fibrosis
Extracellular Matrix
Collagen
Fibroblasts
Magnetic Resonance Imaging
Inflammation
Galectin 3
Macrophage Activation
Transforming Growth Factors
goralatide
Cardiac Myocytes
Genes
Cytoplasm
Radiotherapy
Thorax
Apoptosis

Keywords

  • cardiomyopathies
  • fibrosis
  • inflammation
  • macrophages
  • radiotherapy

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Sharma, U. C., Sonkawade, S. D., Spernyak, J. A., Sexton, S., Nguyen, J., Dahal, S., ... Pokharel, S. (2018). A Small Peptide Ac-SDKP Inhibits Radiation-Induced Cardiomyopathy. Circulation. Heart failure, 11(8), e004867. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004867

A Small Peptide Ac-SDKP Inhibits Radiation-Induced Cardiomyopathy. / Sharma, Umesh C.; Sonkawade, Swati D.; Spernyak, Joseph A.; Sexton, Sandra; Nguyen, Juliane; Dahal, Suraj; Attwood, Kristopher M.; Singh, Anurag K.; van Berlo, Jop; Pokharel, Saraswati.

In: Circulation. Heart failure, Vol. 11, No. 8, 01.08.2018, p. e004867.

Research output: Contribution to journalArticle

Sharma, UC, Sonkawade, SD, Spernyak, JA, Sexton, S, Nguyen, J, Dahal, S, Attwood, KM, Singh, AK, van Berlo, J & Pokharel, S 2018, 'A Small Peptide Ac-SDKP Inhibits Radiation-Induced Cardiomyopathy', Circulation. Heart failure, vol. 11, no. 8, pp. e004867. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004867
Sharma UC, Sonkawade SD, Spernyak JA, Sexton S, Nguyen J, Dahal S et al. A Small Peptide Ac-SDKP Inhibits Radiation-Induced Cardiomyopathy. Circulation. Heart failure. 2018 Aug 1;11(8):e004867. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004867
Sharma, Umesh C. ; Sonkawade, Swati D. ; Spernyak, Joseph A. ; Sexton, Sandra ; Nguyen, Juliane ; Dahal, Suraj ; Attwood, Kristopher M. ; Singh, Anurag K. ; van Berlo, Jop ; Pokharel, Saraswati. / A Small Peptide Ac-SDKP Inhibits Radiation-Induced Cardiomyopathy. In: Circulation. Heart failure. 2018 ; Vol. 11, No. 8. pp. e004867.
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AU - Sexton, Sandra

AU - Nguyen, Juliane

AU - Dahal, Suraj

AU - Attwood, Kristopher M.

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N2 - BACKGROUND: Advances in radiotherapy for thoracic cancers have resulted in improvement of survival. However, radiation exposure to the heart can induce cardiotoxicity. No therapy is currently available to inhibit these untoward effects. We examined whether a small tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), can counteract radiation-induced cardiotoxicity by inhibiting macrophage-dependent inflammatory and fibrotic pathways. METHODS AND RESULTS: After characterizing a rat model of cardiac irradiation with magnetic resonance imaging protocols, we examined the effects of Ac-SDKP in radiation-induced cardiomyopathy. We treated rats with Ac-SDKP for 18 weeks. We then compared myocardial contractile function and extracellular matrix by cardiac magnetic resonance imaging and the extent of inflammation, fibrosis, and Mac-2 (galectin-3) release by tissue analyses. Because Mac-2 is a crucial macrophage-derived mediator of fibrosis, we performed studies to determine Mac-2 synthesis by macrophages in response to radiation, and change in profibrotic responses by Mac-2 gene depleted cardiac fibroblasts after radiation. Cardiac irradiation diminished myocardial contractile velocities and enhanced extracellular matrix deposition. This was accompanied by macrophage infiltration, fibrosis, cardiomyocyte apoptosis, and cardiac Mac-2 expression. Ac-SDKP strongly inhibited these detrimental effects. Ac-SDKP migrated into the perinuclear cytoplasm of the macrophages and inhibited radiation-induced Mac-2 release. Cardiac fibroblasts lacking the Mac-2 gene showed reduced transforming growth factor β1, collagen I, and collagen III expression after radiation exposure. CONCLUSIONS: Our study identifies novel cardioprotective effects of Ac-SDKP in a model of cardiac irradiation. These protective effects are exerted by inhibiting inflammation, fibrosis, and reducing macrophage activation. This study shows a therapeutic potential of this endogenously released peptide to counteract radiation-induced cardiomyopathy.

AB - BACKGROUND: Advances in radiotherapy for thoracic cancers have resulted in improvement of survival. However, radiation exposure to the heart can induce cardiotoxicity. No therapy is currently available to inhibit these untoward effects. We examined whether a small tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), can counteract radiation-induced cardiotoxicity by inhibiting macrophage-dependent inflammatory and fibrotic pathways. METHODS AND RESULTS: After characterizing a rat model of cardiac irradiation with magnetic resonance imaging protocols, we examined the effects of Ac-SDKP in radiation-induced cardiomyopathy. We treated rats with Ac-SDKP for 18 weeks. We then compared myocardial contractile function and extracellular matrix by cardiac magnetic resonance imaging and the extent of inflammation, fibrosis, and Mac-2 (galectin-3) release by tissue analyses. Because Mac-2 is a crucial macrophage-derived mediator of fibrosis, we performed studies to determine Mac-2 synthesis by macrophages in response to radiation, and change in profibrotic responses by Mac-2 gene depleted cardiac fibroblasts after radiation. Cardiac irradiation diminished myocardial contractile velocities and enhanced extracellular matrix deposition. This was accompanied by macrophage infiltration, fibrosis, cardiomyocyte apoptosis, and cardiac Mac-2 expression. Ac-SDKP strongly inhibited these detrimental effects. Ac-SDKP migrated into the perinuclear cytoplasm of the macrophages and inhibited radiation-induced Mac-2 release. Cardiac fibroblasts lacking the Mac-2 gene showed reduced transforming growth factor β1, collagen I, and collagen III expression after radiation exposure. CONCLUSIONS: Our study identifies novel cardioprotective effects of Ac-SDKP in a model of cardiac irradiation. These protective effects are exerted by inhibiting inflammation, fibrosis, and reducing macrophage activation. This study shows a therapeutic potential of this endogenously released peptide to counteract radiation-induced cardiomyopathy.

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