Cardiac mTOR protects the heart against ischemia-reperfusion injury

Toshinori Aoyagi, Yoichiro Kusakari, Chun Yang Xiao, Brendan T. Inouye, Masaya Takahashi, Marielle Scherrer-Crosbie, Anthony Rosenzweig, Kenta Hara, Takashi Matsui

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Cardiac mammalian target of rapamycin (mTOR) is necessary and sufficient to prevent cardiac dysfunction in pathological hypertrophy. However, the role of cardiac mTOR in heart failure after ischemic injury remains undefined. To address this question, we used transgenic (Tg) mice with cardiac-specific overexpression of mTOR (mTOR-Tg mice) to study ischemia-reperfusion (I/R) injury in two animal models: 1) in vivo I/R injury with transient coronary artery ligation and 2) ex vivo I/R injury in Langendorff-perfused hearts with transient global ischemia. At 28 days after I/R, mortality was lower in mTOR-Tg mice than littermate control mice [wild-type (WT) mice]. Echocardiography and MRI demonstrated that global cardiac function in mTOR-Tg mice was preserved, whereas WT mice exhibited significant cardiac dysfunction. Masson's trichrome staining showed that 28 days after I/R, the area of interstitial fibrosis was smaller in mTOR-Tg mice compared with WT mice, suggesting that adverse left ventricular remodeling is inhibited in mTOR-Tg mice. In the ex vivo I/R model, mTOR-Tg hearts demonstrated improved functional recovery compared with WT hearts. Perfusion with Evans blue after ex vivo I/R yielded less staining in mTOR-Tg hearts than WT hearts, indicating that mTOR overexpression inhibited necrosis during I/R injury. Expression of proinflammatory cytokines, including IL-6 and TNF-α, in mTOR-Tg hearts was lower than in WT hearts. Consistent with this, IL-6 in the effluent post-I/R injury was lower in mTOR-Tg hearts than in WT hearts. These findings suggest that cardiac mTOR overexpression in the heart is sufficient to provide substantial cardioprotection against I/R injury and suppress the inflammatory response.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume303
Issue number1
DOIs
StatePublished - Jul 1 2012

Fingerprint

Sirolimus
Reperfusion Injury
Transgenic Mice
Ischemia
Reperfusion
Interleukin-6
Staining and Labeling
Evans Blue
Ventricular Remodeling
Hypertrophy
Ligation
Echocardiography
Coronary Vessels
Fibrosis
Necrosis
Animal Models
Heart Failure
Perfusion

Keywords

  • Heart failure
  • Left ventricular remodeling
  • Myocardial infarction
  • Transgenic mice

ASJC Scopus subject areas

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

Cite this

Aoyagi, T., Kusakari, Y., Xiao, C. Y., Inouye, B. T., Takahashi, M., Scherrer-Crosbie, M., ... Matsui, T. (2012). Cardiac mTOR protects the heart against ischemia-reperfusion injury. American Journal of Physiology - Heart and Circulatory Physiology, 303(1). https://doi.org/10.1152/ajpheart.00241.2012

Cardiac mTOR protects the heart against ischemia-reperfusion injury. / Aoyagi, Toshinori; Kusakari, Yoichiro; Xiao, Chun Yang; Inouye, Brendan T.; Takahashi, Masaya; Scherrer-Crosbie, Marielle; Rosenzweig, Anthony; Hara, Kenta; Matsui, Takashi.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 303, No. 1, 01.07.2012.

Research output: Contribution to journalArticle

Aoyagi, T, Kusakari, Y, Xiao, CY, Inouye, BT, Takahashi, M, Scherrer-Crosbie, M, Rosenzweig, A, Hara, K & Matsui, T 2012, 'Cardiac mTOR protects the heart against ischemia-reperfusion injury', American Journal of Physiology - Heart and Circulatory Physiology, vol. 303, no. 1. https://doi.org/10.1152/ajpheart.00241.2012
Aoyagi, Toshinori ; Kusakari, Yoichiro ; Xiao, Chun Yang ; Inouye, Brendan T. ; Takahashi, Masaya ; Scherrer-Crosbie, Marielle ; Rosenzweig, Anthony ; Hara, Kenta ; Matsui, Takashi. / Cardiac mTOR protects the heart against ischemia-reperfusion injury. In: American Journal of Physiology - Heart and Circulatory Physiology. 2012 ; Vol. 303, No. 1.
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