RGD Reference Report - Carnitine Supplementation Attenuates Sunitinib-Induced Inhibition of AMP-Activated Protein Kinase Downstream Signals in Cardiac Tissues. - Rat Genome Database

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Carnitine Supplementation Attenuates Sunitinib-Induced Inhibition of AMP-Activated Protein Kinase Downstream Signals in Cardiac Tissues.

Authors: Sayed-Ahmed, Mohamed M  Alrufaiq, Badr I  Alrikabi, Ammar  Abdullah, Mashan L  Hafez, Mohamed M  Al-Shabanah, Othman A 
Citation: Sayed-Ahmed MM, etal., Cardiovasc Toxicol. 2019 Aug;19(4):344-356. doi: 10.1007/s12012-018-9500-0.
RGD ID: 329955369
Pubmed: PMID:30644033   (View Abstract at PubMed)
PMCID: PMC6647422   (View Article at PubMed Central)
DOI: DOI:10.1007/s12012-018-9500-0   (Journal Full-text)

This study has been initiated to investigate whether sunitinib (SUN) alters the expression of key genes engaged in mitochondrial transport and oxidation of long chain fatty acids (LCFA), and if so, whether these alterations should be viewed as a mechanism of SUN-induced cardiotoxicity, and to explore the molecular mechanisms whereby carnitine supplementation could attenuate SUN-induced cardiotoxicity. Adult male Wister albino rats were assigned to one of the four treatment groups: Rats in group 1 received no treatment but free access to tap water for 28 days. Rats in group 2 received L-carnitine (200 mg/kg/day) in drinking water for 28 days. Rats in group 3 received SUN (25 mg/kg/day) in drinking water for 28 days. Rats in group 4 received the same doses of L-carnitine and SUN in drinking water for 28 days. Treatment with SUN significantly increased heart weight, cardiac index, and cardiotoxicity enzymatic indices, as well as severe histopathological changes. Moreover, SUN significantly decreased level of adenosine monophosphate-activated protein kinase (AMPKα2), total carnitine, adenosine triphosphate (ATP) and carnitine palmitoyltransferase I (CPT I) expression and significantly increased acetyl-CoA carboxylase-2 (ACC2) expression and malonyl-CoA level in cardiac tissues. Interestingly, carnitine supplementation resulted in a complete reversal of all the biochemical, gene expression and histopathological changes-induced by SUN to the control values. In conclusion, data from this study suggest that SUN inhibits AMPK downstream signaling with the consequent inhibition of mitochondrial transport of LCFA and energy production in cardiac tissues. Carnitine supplementation attenuates SUN-induced cardiotoxicity.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ACACBHumanCardiac Fibrosis  ISOAcacb (Rattus norvegicus)mRNA and protein:increased expression:heart (rat)RGD 
AcacbMouseCardiac Fibrosis  ISOAcacb (Rattus norvegicus)mRNA and protein:increased expression:heart (rat)RGD 
AcacbRatCardiac Fibrosis  IEP mRNA and protein:increased expression:heart (rat)RGD 
CPT1AHumanCardiac Fibrosis  ISOCpt1a (Rattus norvegicus)mRNA and protein:decreased expression:heart (rat)RGD 
Cpt1aRatCardiac Fibrosis  IEP mRNA and protein:decreased expression:heart (rat)RGD 
Cpt1aMouseCardiac Fibrosis  ISOCpt1a (Rattus norvegicus)mRNA and protein:decreased expression:heart (rat)RGD 
MLYCDHumanCardiac Fibrosis  ISOMlycd (Rattus norvegicus)protein:increased expression:heart (rat)RGD 
MlycdMouseCardiac Fibrosis  ISOMlycd (Rattus norvegicus)protein:increased expression:heart (rat)RGD 
MlycdRatCardiac Fibrosis  IEP protein:increased expression:heart (rat)RGD 
PRKAA2HumanCardiac Fibrosis  ISOPrkaa2 (Rattus norvegicus)protein:decreased expression:serum and heart (rat)RGD 
Prkaa2RatCardiac Fibrosis  IEP protein:decreased expression:serum and heart (rat)RGD 
Prkaa2MouseCardiac Fibrosis  ISOPrkaa2 (Rattus norvegicus)protein:decreased expression:serum and heart (rat)RGD 
ACACBHumanCardiotoxicity  ISOAcacb (Rattus norvegicus)mRNA and protein:increased expression:heart (rat)RGD 
AcacbMouseCardiotoxicity  ISOAcacb (Rattus norvegicus)mRNA and protein:increased expression:heart (rat)RGD 
AcacbRatCardiotoxicity  IEP mRNA and protein:increased expression:heart (rat)RGD 
CPT1AHumanCardiotoxicity  ISOCpt1a (Rattus norvegicus)mRNA and protein:decreased expression:heart (rat)RGD 
Cpt1aRatCardiotoxicity  IEP mRNA and protein:decreased expression:heart (rat)RGD 
Cpt1aMouseCardiotoxicity  ISOCpt1a (Rattus norvegicus)mRNA and protein:decreased expression:heart (rat)RGD 
MLYCDHumanCardiotoxicity  ISOMlycd (Rattus norvegicus)protein:increased expression:heart (rat)RGD 
MlycdMouseCardiotoxicity  ISOMlycd (Rattus norvegicus)protein:increased expression:heart (rat)RGD 
MlycdRatCardiotoxicity  IEP protein:increased expression:heart (rat)RGD 
PRKAA2HumanCardiotoxicity  ISOPrkaa2 (Rattus norvegicus)protein:decreased expression:serum and heart (rat)RGD 
Prkaa2RatCardiotoxicity  IEP protein:decreased expression:serum and heart (rat)RGD 
Prkaa2MouseCardiotoxicity  ISOPrkaa2 (Rattus norvegicus)protein:decreased expression:serum and heart (rat)RGD 

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ACACBHumancarnitine decreases expression ISOAcacb (Rattus norvegicus)L-carnitine decreases expression of Acacb mRNA and protein in rat heartRGD 
AcacbRatcarnitine decreases expression EXP L-carnitine decreases expression of Acacb mRNA and protein in rat heartRGD 
AcacbMousecarnitine decreases expression ISOAcacb (Rattus norvegicus)L-carnitine decreases expression of Acacb mRNA and protein in rat heartRGD 
CPT1AHumancarnitine increases expression ISOCpt1a (Rattus norvegicus)L-carnitine increases expression of Cpt1a mRNA and protein in rat heartRGD 
CPT1AHumancarnitine multiple interactionsISOCpt1a (Rattus norvegicus)L-carnitine inhibits the reaction [sunitinib decreases expression of Cpt1a mRNA and protein in rat heart]RGD 
Cpt1aRatcarnitine increases expression EXP L-carnitine increases expression of Cpt1a mRNA and protein in rat heartRGD 
Cpt1aRatcarnitine multiple interactionsEXP L-carnitine inhibits the reaction [sunitinib decreases expression of Cpt1a mRNA and protein in rat heart]RGD 
Cpt1aMousecarnitine increases expression ISOCpt1a (Rattus norvegicus)L-carnitine increases expression of Cpt1a mRNA and protein in rat heartRGD 
Cpt1aMousecarnitine multiple interactionsISOCpt1a (Rattus norvegicus)L-carnitine inhibits the reaction [sunitinib decreases expression of Cpt1a mRNA and protein in rat heart]RGD 
MLYCDHumancarnitine increases expression ISOMlycd (Rattus norvegicus)L-carnitine increases expression of Mlycd protein in rat heartRGD 
MLYCDHumancarnitine multiple interactionsISOMlycd (Rattus norvegicus)L-carnitine inhibits the reaction [sunitinib increases expression of Mlycd protein in rat heart]RGD 
MlycdRatcarnitine increases expression EXP L-carnitine increases expression of Mlycd protein in rat heartRGD 
MlycdMousecarnitine multiple interactionsISOMlycd (Rattus norvegicus)L-carnitine inhibits the reaction [sunitinib increases expression of Mlycd protein in rat heart]RGD 
MlycdMousecarnitine increases expression ISOMlycd (Rattus norvegicus)L-carnitine increases expression of Mlycd protein in rat heartRGD 
MlycdRatcarnitine multiple interactionsEXP L-carnitine inhibits the reaction [sunitinib increases expression of Mlycd protein in rat heart]RGD 
PRKAA2Humancarnitine increases expression ISOPrkaa2 (Rattus norvegicus)L-carnitine increases expression of Ampka2 protein in rat serum and heartRGD 
PRKAA2Humancarnitine multiple interactionsISOPrkaa2 (Rattus norvegicus)L-carnitine inhibits the reaction [sunitinib decreases expression of Ampka2 protein in rat serum and heart]RGD 
Prkaa2Ratcarnitine increases expression EXP L-carnitine increases expression of Ampka2 protein in rat serum and heartRGD 
Prkaa2Ratcarnitine multiple interactionsEXP L-carnitine inhibits the reaction [sunitinib decreases expression of Ampka2 protein in rat serum and heart]RGD 
Prkaa2Mousecarnitine increases expression ISOPrkaa2 (Rattus norvegicus)L-carnitine increases expression of Ampka2 protein in rat serum and heartRGD 
Prkaa2Mousecarnitine multiple interactionsISOPrkaa2 (Rattus norvegicus)L-carnitine inhibits the reaction [sunitinib decreases expression of Ampka2 protein in rat serum and heart]RGD 
ACACBHumansunitinib increases expression ISOAcacb (Rattus norvegicus)sunitinib increases expression of Acacb mRNA and protein in rat heartRGD 
AcacbMousesunitinib increases expression ISOAcacb (Rattus norvegicus)sunitinib increases expression of Acacb mRNA and protein in rat heartRGD 
AcacbRatsunitinib increases expression EXP sunitinib increases expression of Acacb mRNA and protein in rat heartRGD 
CPT1AHumansunitinib decreases expression ISOCpt1a (Rattus norvegicus)sunitinib decreases expression of Cpt1a mRNA and protein in rat heartRGD 
Cpt1aRatsunitinib decreases expression EXP sunitinib decreases expression of Cpt1a mRNA and protein in rat heartRGD 
Cpt1aMousesunitinib decreases expression ISOCpt1a (Rattus norvegicus)sunitinib decreases expression of Cpt1a mRNA and protein in rat heartRGD 
MLYCDHumansunitinib increases expression ISOMlycd (Rattus norvegicus)sunitinib increases expression of Mlycd protein in rat heartRGD 
MlycdMousesunitinib increases expression ISOMlycd (Rattus norvegicus)sunitinib increases expression of Mlycd protein in rat heartRGD 
MlycdRatsunitinib increases expression EXP sunitinib increases expression of Mlycd protein in rat heartRGD 
PRKAA2Humansunitinib decreases expression ISOPrkaa2 (Rattus norvegicus)sunitinib decreases expression of Ampka2 protein in rat serum and heartRGD 
Prkaa2Ratsunitinib decreases expression EXP sunitinib decreases expression of Ampka2 protein in rat serum and heartRGD 
Prkaa2Mousesunitinib decreases expression ISOPrkaa2 (Rattus norvegicus)sunitinib decreases expression of Ampka2 protein in rat serum and heartRGD 

Objects Annotated

Genes (Rattus norvegicus)
Acacb  (acetyl-CoA carboxylase beta)
Cpt1a  (carnitine palmitoyltransferase 1A)
Mlycd  (malonyl-CoA decarboxylase)
Prkaa2  (protein kinase AMP-activated catalytic subunit alpha 2)

Genes (Mus musculus)
Acacb  (acetyl-Coenzyme A carboxylase beta)
Cpt1a  (carnitine palmitoyltransferase 1a, liver)
Mlycd  (malonyl-CoA decarboxylase)
Prkaa2  (protein kinase, AMP-activated, alpha 2 catalytic subunit)

Genes (Homo sapiens)
ACACB  (acetyl-CoA carboxylase beta)
CPT1A  (carnitine palmitoyltransferase 1A)
MLYCD  (malonyl-CoA decarboxylase)
PRKAA2  (protein kinase AMP-activated catalytic subunit alpha 2)


Additional Information