Protective effects of the mechanistic target of rapamycin against excess iron and ferroptosis in cardiomyocytes

Yuichi Baba, Jason K. Higa, Briana K. Shimada, Kate M. Horiuchi, Tomohiro Suhara, Motoi Kobayashi, Jonathan D. Woo, Hiroko Aoyagi, Karra S. Marh, Hiroaki Kitaoka, Takashi Matsui

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Clinical studies have suggested that myocardial iron is a risk factor for left ventricular remodeling in patients after myocardial infarction. Ferroptosis has recently been reported as a mechanism of iron-dependent nonapoptotic cell death. However, ferroptosis in the heart is not well understood. Mechanistic target of rapamycin (mTOR) protects the heart against pathological stimuli such as ischemia. To define the role of cardiac mTOR on cell survival in iron-mediated cell death, we examined cardiomyocyte (CM) cell viability under excess iron and ferroptosis conditions. Adult mouse CMs were isolated from cardiac-specific mTOR transgenic mice, cardiac-specific mTOR knockout mice, or control mice. CMs were treated with ferric iron [Fe(III)]-citrate, erastin, a class 1 ferroptosis inducer, or Ras-selective lethal 3 (RSL3), a class 2 ferroptosis inducer. Live/dead cell viability assays revealed that Fe(III)-citrate, erastin, and RSL3 induced cell death. Cotreatment with ferrostatin-1, a ferroptosis inhibitor, inhibited cell death in all conditions. mTOR overexpression suppressed Fe(III)-citrate, erastin, and RSL3-induced cell death, whereas mTOR deletion exaggerated cell death in these conditions. 2’,7’-Dichlorodihydrofluorescein diacetate measurement of reactive oxygen species (ROS) production showed that erastin-induced ROS production was significantly lower in mTOR transgenic versus control CMs. These findings suggest that ferroptosis is a significant type of cell death in CMs and that mTOR plays an important role in protecting CMs against excess iron and ferroptosis, at least in part, by regulating ROS production. Understanding the effects of mTOR in preventing iron-mediated cell death will provide a new therapy for patients with myocardial infarction. NEW & NOTEWORTHY Ferroptosis has recently been reported as a new form of iron-dependent nonapoptotic cell death. However, ferroptosis in the heart is not well characterized. Using cultured adult mouse cardiomyocytes, we demonstrated that the mechanistic target of rapamycin plays an important role in protecting cardiomyocytes against excess iron and ferroptosis.

Original languageEnglish
Pages (from-to)H659-H668
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume314
Issue number3
DOIs
Publication statusPublished - 2018 Apr 1

Fingerprint

Sirolimus
Cardiac Myocytes
Iron
Cell Death
Reactive Oxygen Species
Cell Survival
Citric Acid
Myocardial Infarction
Ventricular Remodeling
Knockout Mice
Transgenic Mice
Ischemia
erastin

Keywords

  • Cardiomyocyte
  • Ferroptosis
  • Iron
  • Mechanistic target of rapamycin

ASJC Scopus subject areas

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

Cite this

Protective effects of the mechanistic target of rapamycin against excess iron and ferroptosis in cardiomyocytes. / Baba, Yuichi; Higa, Jason K.; Shimada, Briana K.; Horiuchi, Kate M.; Suhara, Tomohiro; Kobayashi, Motoi; Woo, Jonathan D.; Aoyagi, Hiroko; Marh, Karra S.; Kitaoka, Hiroaki; Matsui, Takashi.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 314, No. 3, 01.04.2018, p. H659-H668.

Research output: Contribution to journalArticle

Baba, Y, Higa, JK, Shimada, BK, Horiuchi, KM, Suhara, T, Kobayashi, M, Woo, JD, Aoyagi, H, Marh, KS, Kitaoka, H & Matsui, T 2018, 'Protective effects of the mechanistic target of rapamycin against excess iron and ferroptosis in cardiomyocytes', American Journal of Physiology - Heart and Circulatory Physiology, vol. 314, no. 3, pp. H659-H668. https://doi.org/10.1152/ajpheart.00452.2017
Baba, Yuichi ; Higa, Jason K. ; Shimada, Briana K. ; Horiuchi, Kate M. ; Suhara, Tomohiro ; Kobayashi, Motoi ; Woo, Jonathan D. ; Aoyagi, Hiroko ; Marh, Karra S. ; Kitaoka, Hiroaki ; Matsui, Takashi. / Protective effects of the mechanistic target of rapamycin against excess iron and ferroptosis in cardiomyocytes. In: American Journal of Physiology - Heart and Circulatory Physiology. 2018 ; Vol. 314, No. 3. pp. H659-H668.
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