sirolimus and Atrial-Remodeling

Aging is accompanied with unfavorable geometric and functional changes in the heart involving dysregulation of Akt and autophagy. This study examined the impact of Akt2 ablation on life span and cardiac aging as well as the mechanisms involved with a focus on autophagy and mitochondrial integrity. Cardiac geometry, contractile, and intracellular Ca

Topics: Adaptation, Physiological; Animals; Atrial Remodeling; Autophagy; Autophagy-Related Protein 7; Beclin-1; Calcium; Cardiomegaly; Forkhead Box Protein O1; Gene Expression Regulation; Heterocyclic Compounds, 4 or More Rings; Longevity; Male; Membrane Proteins; Mice; Mice, Knockout; Microtubule-Associated Proteins; Mitochondria; Mitochondrial Proteins; Myocardial Contraction; Myocardium; Phosphorylation; Protein Kinases; Proto-Oncogene Proteins c-akt; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction; Sirolimus; Sirtuin 1

Cardiac hypertrophy is closely linked to impaired fatty acid oxidation, but the molecular basis of this link is unclear. Here, we investigated the loss of an obligate enzyme in mitochondrial long-chain fatty acid oxidation, carnitine palmitoyltransferase 2 (CPT2), on muscle and heart structure, function, and molecular signatures in a muscle- and heart-specific CPT2-deficient mouse (Cpt2

Topics: Acetylation; Animals; Atrial Remodeling; Cardiomegaly; Carnitine O-Palmitoyltransferase; Crosses, Genetic; Diet, Ketogenic; Drug Resistance; Enzyme Activation; Heart; Histone Deacetylase Inhibitors; Male; Mechanistic Target of Rapamycin Complex 1; Metabolism, Inborn Errors; Mice, Knockout; Mice, Transgenic; Mitochondria, Heart; Myocardium; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Sirolimus; Specific Pathogen-Free Organisms; Survival Analysis

Adaptive cardiac remodeling is characterized by enhanced signaling of mTORC2 downstream kinase Akt. In females, 17ß-estradiol (E2), as well as Akt contribute essentially to sex-related premenopausal cardioprotection. Pharmacologic mTOR targeting with rapamycin is increasingly used for various clinical indications, yet burdened with clinical heterogeneity in therapy responses. The drug inhibits mTORC1 and less-so mTORC2. In male rodents, rapamycin decreases maladaptive cardiac hypertrophy whereas it leads to detrimental dilative cardiomyopathy in females. We hypothesized that mTOR inhibition could interfere with 17β-estradiol (E2)-mediated sexual dimorphism and adaptive cell growth and tested responses in murine female hearts and cultured female cardiomyocytes. Under physiological in vivo conditions, rapamycin compromised mTORC2 function only in female, but not in male murine hearts. In cultured female cardiomyocytes, rapamycin impaired simultaneously IGF-1 induced activation of both mTOR signaling branches, mTORC1 and mTORC2 only in presence of E2. Use of specific estrogen receptor (ER)α- and ERβ-agonists indicated involvement of both estrogen receptors (ER) in rapamycin effects on mTORC1 and mTORC2. Classical feedback mechanisms common in tumour cells with upregulation of PI3K signaling were not involved. E2 effect on Akt-pS473 downregulation by rapamycin was independent of ERK as shown by sequential mTOR and MEK-inhibition. Furthermore, regulatory mTORC2 complex defining component rictor phosphorylation at Ser1235, known to interfere with Akt-substrate binding to mTORC2, was not altered. Functionally, rapamycin significantly reduced trophic effect of E2 on cell size. In addition, cardiomyocytes with reduced Akt-pS473 under rapamycin treatment displayed decreased SERCA2A mRNA and protein expression suggesting negative functional consequences on cardiomyocyte contractility. Rictor silencing confirmed regulation of SERCA2A expression by mTORC2 in E2-cultured female cardiomyocytes. These data highlight a novel modulatory function of E2 on rapamycin effect on mTORC2 in female cardiomyocytes and regulation of SERCA2A expression by mTORC2. Conceivably, rapamycin abrogates the premenopausal "female advantage".

Topics: Animals; Atrial Remodeling; Carrier Proteins; Cells, Cultured; Estradiol; Female; Heart; Male; Mechanistic Target of Rapamycin Complex 2; Mice, Inbred C57BL; Multiprotein Complexes; Myocardium; Myocytes, Cardiac; Phosphorylation; Rapamycin-Insensitive Companion of mTOR Protein; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sirolimus; TOR Serine-Threonine Kinases