mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Inflammation Research

Background:

• Mammalian target of rapamycin (mTOR) inhibition by rapamycin is known to suppress myocardial hypertrophy.
• The precise role of mTOR in pathological cardiac dysfunction and its regulation of inflammatory responses remain incompletely understood.
• Rapamycin has been reported to enhance inflammation under specific conditions, complicating its role in heart failure.

Purpose of the Study:

• To investigate the influence of mammalian target of rapamycin (mTOR) on pathological cardiac hypertrophy and dysfunction.
• To determine if cardiac mTOR signaling regulates the inflammatory response during pressure overload.
• To elucidate the cardioprotective mechanisms of mTOR in the context of heart failure progression.

Main Methods:

• Generation of transgenic mice with cardiac-specific overexpression of wild-type mTOR (mTOR-Tg).
• Induction of left ventricular pressure overload using transverse aortic constriction (TAC) in mTOR-Tg and wild-type (WT) littermate controls.
• Assessment of cardiac function, interstitial fibrosis, and expression of pro-inflammatory cytokines (IL-1β, IL-6).
• In vitro studies using HL-1 cardiomyocytes exposed to lipopolysaccharide (LPS) with mTOR overexpression and/or mTOR inhibitors (rapamycin, PP242).

Main Results:

• mTOR-Tg mice exhibited protection against cardiac dysfunction and reduced interstitial fibrosis following TAC compared to WT mice.
• WT mice showed significantly increased pro-inflammatory cytokines (IL-1β, IL-6) post-TAC, whereas mTOR-Tg mice did not.
• In vitro, mTOR overexpression suppressed LPS-induced IL-6 secretion in cardiomyocytes, an effect abolished by mTOR inhibitors.
• mTOR overexpression was found to reduce NF-κB-regulated transcription in HL-1 cells.

Conclusions:

• Cardiac-specific overexpression of mammalian target of rapamycin (mTOR) mitigates adverse outcomes associated with pressure overload-induced cardiac hypertrophy.
• The cardioprotective effects of mTOR appear to be mediated through the regulation of inflammatory responses, specifically by suppressing pro-inflammatory cytokine production.
• These findings highlight mTOR as a potential therapeutic target for managing pathological cardiac hypertrophy and heart failure.