RGD Reference Report - Rapamycin treatment augments both protein ubiquitination and Akt activation in pressure-overloaded rat myocardium. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Rapamycin treatment augments both protein ubiquitination and Akt activation in pressure-overloaded rat myocardium.

Authors: Harston, RK  McKillop, JC  Moschella, PC  Van Laer, A  Quinones, LS  Baicu, CF  Balasubramanian, S  Zile, MR  Kuppuswamy, D 
Citation: Harston RK, etal., Am J Physiol Heart Circ Physiol. 2011 May;300(5):H1696-706. doi: 10.1152/ajpheart.00545.2010. Epub 2011 Feb 25.
RGD ID: 10041003
Pubmed: PMID:21357504   (View Abstract at PubMed)
PMCID: PMC3094075   (View Article at PubMed Central)
DOI: DOI:10.1152/ajpheart.00545.2010   (Journal Full-text)

Ubiquitin-mediated protein degradation is necessary for both increased ventricular mass and survival signaling for compensated hypertrophy in pressure-overloaded (PO) myocardium. Another molecular keystone involved in the hypertrophic growth process is the mammalian target of rapamycin (mTOR), which forms two distinct functional complexes: mTORC1 that activates p70S6 kinase-1 to enhance protein synthesis and mTORC2 that activates Akt to promote cell survival. Independent studies in animal models show that rapamycin treatment that alters mTOR complexes also reduces hypertrophic growth and increases lifespan by an unknown mechanism. We tested whether the ubiquitin-mediated regulation of growth and survival in hypertrophic myocardium is linked to the mTOR pathway. For in vivo studies, right ventricle PO in rats was conducted by pulmonary artery banding; the normally loaded left ventricle served as an internal control. Rapamycin (0.75 mg/kg per day) or vehicle alone was administered intraperitoneally for 3 days or 2 wk. Immunoblot and immunofluorescence imaging showed that the level of ubiquitylated proteins in cardiomyocytes that increased following 48 h of PO was enhanced by rapamycin. Rapamycin pretreatment also significantly increased PO-induced Akt phosphorylation at S473, a finding confirmed in cardiomyocytes in vitro to be downstream of mTORC2. Analysis of prosurvival signaling in vivo showed that rapamycin increased PO-induced degradation of phosphorylated inhibitor of kappaB, enhanced expression of cellular inhibitor of apoptosis protein 1, and decreased active caspase-3. Long-term rapamycin treatment in 2-wk PO myocardium blunted hypertrophy, improved contractile function, and reduced caspase-3 and calpain activation. These data indicate potential cardioprotective benefits of rapamycin in PO hypertrophy.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of protein phosphorylation  IMP 10041003 RGD 
negative regulation of protein ubiquitination  IMP 10041003 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Akt1  (AKT serine/threonine kinase 1)
Mtor  (mechanistic target of rapamycin kinase)

Genes (Mus musculus)
Akt1  (thymoma viral proto-oncogene 1)
Mtor  (mechanistic target of rapamycin kinase)

Genes (Homo sapiens)
AKT1  (AKT serine/threonine kinase 1)
MTOR  (mechanistic target of rapamycin kinase)


Additional Information