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

Abstract

Previous studies have suggested that inhibition of the mammalian target of rapamycin (mTOR) by rapamycin suppresses myocardial hypertrophy. However, the role of mTOR in the progression of cardiac dysfunction in pathological hypertrophy has not been fully defined. Interestingly, recent reports indicate that the inflammatory response, which plays an important role in the development of heart failure, is enhanced by rapamycin under certain conditions. Our aim in this study was to determine the influence of mTOR on pathological hypertrophy and to assess whether cardiac mTOR regulates the inflammatory response. We generated transgenic mice with cardiac-specific overexpression of wild-type mTOR (mTOR-Tg). mTOR-Tg mice were protected against cardiac dysfunction following left ventricular pressure overload induced by transverse aortic constriction (TAC) (P < 0.01) and had significantly less interstitial fibrosis compared with littermate controls (WT) at 4 wk post-TAC (P < 0.01). In contrast, TAC caused cardiac dysfunction in WT. At 1 wk post-TAC, the proinflammatory cytokines interleukin (IL)-1β and IL-6 were significantly increased in WT mice but not in mTOR-Tg mice. To further characterize the effects of mTOR activation, we exposed HL-1 cardiomyocytes transfected with mTOR to lipopolysaccharide (LPS). mTOR overexpression suppressed LPS-induced secretion of IL-6 (P < 0.001), and the mTOR inhibitors rapamycin and PP242 abolished this inhibitory effect of mTOR. In addition, mTOR overexpression reduced NF-κB-regulated transcription in HL-1 cells. These data suggest that mTOR mitigates adverse outcomes of pressure overload and that this cardioprotective effect of mTOR is mediated by regulation of the inflammatory reaction.

Deletion of MLIP (Muscle-enriched A-type Lamin-interacting Protein) Leads to Cardiac Hyperactivation of Akt/Mammalian Target of Rapamycin (mTOR) and Impaired Cardiac Adaptation

“…5C) is comparable to the levels reported in mouse models that do not explicit cardiac hypertrophy (45)(46)(47). Interestingly, the ␣-MHC-mTOR transgenic mice have normal cardiac structure and function but a limited response to cardiac stress (aortic banding) (47), as observed in Mlip Ϫ/Ϫ mice under chronic isoproterenol infusion.…”

“…Conversely, the activation of mTOR has also been reported in several mouse models without hypertrophy at the organ or cellular level (45,46). Noteworthy, the activation of mTOR alone is not sufficient to induce cardiac hypertrophy and morphological changes, as evidenced by the absence of myocardial structural changes in mice overexpressing mTOR in cardiomyocytes (47). It appears that the addition of stress (e.g.…”

Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion

“…Our previous study (5), which used transgenic mice (Tg) with cardiac-specific overexpression of mTOR (mTOR-Tg mice), demonstrated that cardiac mTOR is sufficient to protect the heart against ischemia-reperfusion (I/R) injury in both in vivo and ex vivo models (5). We confirmed that both mTORC1 and mTORC2 are almost equally activated in mTOR-Tg mice (45).…”

“…Tg mice expressing hemagglutinin-tagged wild-type (WT) rat mTOR under the direction of the murine ␣-myosin heavy chain promoter have been previously described in detail (45). Line 4 male (mTOR-Tg) mice, in which mTOR expression was about threefold higher than littermate controls (WT mice) (45), were used for these experiments. Male WT and mTOR-Tg mice at 6 wk of age were fed a HFD for 12 wk and weighed once a week until they reached 18 wk of age.…”

Carboxyl‐Terminal Modulator Protein Ameliorates Pathological Cardiac Hypertrophy by Suppressing the Protein Kinase B Signaling Pathway

“…When activated, AKT phosphorylates its downstream molecules mTOR and GSK3β via the phosphorylation of tuberous sclerosis complex and the inactivation of Ras homolog enriched in brain; mTOR phosphorylates P70S6K 27, 28. Furthermore, the expression of mTOR is increased in the cardiac tissue of patients with heart failure compared with healthy controls 29. The inhibition of mTOR with rapamycin could ameliorate pathological cardiac hypertrophy in humans and in animal models induced by pressure overload 30, 31.…”