Extracellular matrix in cardiovascular pathophysiology: Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice

Qing Qin, Hemal Mehta, Kelvin Yen, Gerardo Navarrete, Sebastian Brandhorst, Junxiang Wan, Silvia Delrio, Xin Zhang, Lilach O Lerman, Pinchas Cohen, Amir Lerman

Research output: Contribution to journalArticle

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Abstract

Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin (HN) is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. The present study aimed to test the hypothesis that chronic supplementation of exogenous HN in middle-aged mice could prevent and reverse cardiac fibrosis and apoptosis in the aging heart. Female C57BL/6N mice at 18 mo of age received 14-mo intraperitoneal injections of vehicle (old group; n = 6) or HN analog (HNG; 4 mg/kg 2 times/wk, old + HNG group, n = 8) and were euthanized at 32 mo of age. C57BL/6N female mice (young group, n = 5) at 5 mo of age were used as young controls. HNG treatment significantly increased the ratio of cardiomyocytes to fibroblasts in aging hearts, as shown by the percentage of each cell type in randomly chosen fields after immunofluorescence staining. Furthermore, the increased collagen deposition in aged hearts was significantly reduced after HNG treatment, as indicated by picrosirius red staining. HNG treatment also reduced in aging mice cardiac fibroblast proliferation (5'-bromo-2-deoxyuridine staining) and attenuated transforming growth factor-β1, fibroblast growth factor-2, and matrix metalloproteinase-2 expression (immunohistochemistry or real-time PCR). Myocardial apoptosis was inhibited in HNG-treated aged mice (TUNEL staining). To decipher the pathway involved in the attenuation of the myocardial fibrosis by HNG, Western blot analysis was done and showed that HNG upregulated the Akt/ glycogen synthase kinase-3β pathway in aged mice. Exogenous HNG treatment attenuated myocardial fibrosis and apoptosis in aged mice. The results of the present study suggest a role for the mitochondria-derived peptide HN in the cardioprotection associated with aging. NEW & NOTEWORTHY Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. Here, we demonstrate, for the first time, that exogenous humanin treatment attenuated myocardial fibrosis and apoptosis in aging mice. We also detected upregulated Akt/glycogen synthase kinase-3β pathway in humanin analog-treated mice, which might be the mechanism involved in the cardioprotective effect of humanin analog in aging mice.

Original languageEnglish (US)
Pages (from-to)H1127-H1136
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume315
Issue number5
DOIs
StatePublished - Oct 1 2018

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Extracellular Matrix
Fibrosis
Peptides
Apoptosis
Staining and Labeling
Glycogen Synthase Kinase 3
Biological Phenomena
Mitochondria
Therapeutics
Oxidative Stress
Fibroblasts
humanin
Matrix Metalloproteinase 2
In Situ Nick-End Labeling
Transforming Growth Factors
Fibroblast Growth Factor 2
Bromodeoxyuridine
Intraperitoneal Injections
Inbred C57BL Mouse
Cardiac Myocytes

Keywords

  • Aging
  • Humanin
  • Myocardial fibrosis

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Extracellular matrix in cardiovascular pathophysiology : Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice. / Qin, Qing; Mehta, Hemal; Yen, Kelvin; Navarrete, Gerardo; Brandhorst, Sebastian; Wan, Junxiang; Delrio, Silvia; Zhang, Xin; Lerman, Lilach O; Cohen, Pinchas; Lerman, Amir.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 315, No. 5, 01.10.2018, p. H1127-H1136.

Research output: Contribution to journalArticle

Qin, Qing ; Mehta, Hemal ; Yen, Kelvin ; Navarrete, Gerardo ; Brandhorst, Sebastian ; Wan, Junxiang ; Delrio, Silvia ; Zhang, Xin ; Lerman, Lilach O ; Cohen, Pinchas ; Lerman, Amir. / Extracellular matrix in cardiovascular pathophysiology : Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice. In: American Journal of Physiology - Heart and Circulatory Physiology. 2018 ; Vol. 315, No. 5. pp. H1127-H1136.
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AU - Wan, Junxiang

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