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Cardioprotective Signature of Short-Term Caloric Restriction.

Noyan H, El-Mounayri O, Isserlin R, Arab S, Momen A, Cheng HS, Wu J, Afroze T, Li RK, Fish JE, Bader GD, Husain M - PLoS ONE (2015)

Bottom Line: This short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). mRNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM).Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3ß, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1α, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38).CR regimen was also associated with reduced protein abundance of cleaved caspase 3 in the infarcted heart and improved cardiac function.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, Ontario, Canada.

ABSTRACT

Objective: To understand the molecular pathways underlying the cardiac preconditioning effect of short-term caloric restriction (CR).

Background: Lifelong CR has been suggested to reduce the incidence of cardiovascular disease through a variety of mechanisms. However, prolonged adherence to a CR life-style is difficult. Here we reveal the pathways that are modulated by short-term CR, which are associated with protection of the mouse heart from ischemia.

Methods: Male 10-12 wk old C57bl/6 mice were randomly assigned to an ad libitum (AL) diet with free access to regular chow, or CR, receiving 30% less food for 7 days (d), prior to myocardial infarction (MI) via permanent coronary ligation. At d8, the left ventricles (LV) of AL and CR mice were collected for Western blot, mRNA and microRNA (miR) analyses to identify cardioprotective gene expression signatures. In separate groups, infarct size, cardiac hemodynamics and protein abundance of caspase 3 was measured at d2 post-MI.

Results: This short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). mRNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM). Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3ß, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1α, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38). CR regimen was also associated with reduced protein abundance of cleaved caspase 3 in the infarcted heart and improved cardiac function.

No MeSH data available.


Related in: MedlinePlus

Short-term CR is associated with robust changes in LV gene expression profile.Principal Component Analysis (PCA) depicting overall data. (A) PCA representation of replicates to visualize overall clustering of the microarray gene expression profiles of CR (blue mesh) and Ad lib (green mesh) containing 5 replicate samples (red) in each group. PCA depicts complete separation of overall pattern in CR vs. Ad lib (AL) samples, (B) The genes differentially expressed (upregulated or downregulated in the CR relative to AL) are clustered according to treatment group. The color gradient (red, up-regulation; green, down-regulation) represents normalized gene expression of each gene in all of the samples listed on the right side of each row. The dendrogram on the left shows the grouping of samples based on the similarity of gene expressions amongst them. Samples were clearly grouped according to CR treatment.
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pone.0130658.g003: Short-term CR is associated with robust changes in LV gene expression profile.Principal Component Analysis (PCA) depicting overall data. (A) PCA representation of replicates to visualize overall clustering of the microarray gene expression profiles of CR (blue mesh) and Ad lib (green mesh) containing 5 replicate samples (red) in each group. PCA depicts complete separation of overall pattern in CR vs. Ad lib (AL) samples, (B) The genes differentially expressed (upregulated or downregulated in the CR relative to AL) are clustered according to treatment group. The color gradient (red, up-regulation; green, down-regulation) represents normalized gene expression of each gene in all of the samples listed on the right side of each row. The dendrogram on the left shows the grouping of samples based on the similarity of gene expressions amongst them. Samples were clearly grouped according to CR treatment.

Mentions: Microarray analysis was conducted to examine the global LV gene expression profile underlying the demonstrated preconditioning effect of short-term CR. The gene-expression patterns of CR and AL mice were compared using MOE 430.2 Affymetrix Gene Chip Array. A total of 6977 transcripts were significantly regulated (unpaired T-test corrected P≤0.05 false discovery rate (FDR) Benjamini-Hochberg), with 115 genes showing ≥2-fold up-or down-regulation in CR vs. AL. Both principal component analysis (PCA) and hierarchical clustering (heat maps) demonstrated clear differences in global gene expression between the two groups (Fig 3A and 3B). We also conducted quantitative PCR (qPCR) validation of several genes that were differentially regulated in the array of CR vs. AL (Fig. B in S2 File). To identify pathways and processes that were enriched with differentially regulated genes in CR vs. AL, we next conducted a GSEA (Fig 4). Pathways associated with ECM remodeling, angiogenesis, cell morphology, migration and immune response were down-regulated in CR. Interestingly, there was high enrichment in pathways associated with anti-oxidative stress, circadian rhythmicity and biological clock, which have been previously described in life-long CR studies [13, 23, 32]. Our results demonstrate that short-term CR for only 7d promotes global changes in cardiac gene expression, resembling in part what has been described in long-term CR.


Cardioprotective Signature of Short-Term Caloric Restriction.

Noyan H, El-Mounayri O, Isserlin R, Arab S, Momen A, Cheng HS, Wu J, Afroze T, Li RK, Fish JE, Bader GD, Husain M - PLoS ONE (2015)

Short-term CR is associated with robust changes in LV gene expression profile.Principal Component Analysis (PCA) depicting overall data. (A) PCA representation of replicates to visualize overall clustering of the microarray gene expression profiles of CR (blue mesh) and Ad lib (green mesh) containing 5 replicate samples (red) in each group. PCA depicts complete separation of overall pattern in CR vs. Ad lib (AL) samples, (B) The genes differentially expressed (upregulated or downregulated in the CR relative to AL) are clustered according to treatment group. The color gradient (red, up-regulation; green, down-regulation) represents normalized gene expression of each gene in all of the samples listed on the right side of each row. The dendrogram on the left shows the grouping of samples based on the similarity of gene expressions amongst them. Samples were clearly grouped according to CR treatment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476723&req=5

pone.0130658.g003: Short-term CR is associated with robust changes in LV gene expression profile.Principal Component Analysis (PCA) depicting overall data. (A) PCA representation of replicates to visualize overall clustering of the microarray gene expression profiles of CR (blue mesh) and Ad lib (green mesh) containing 5 replicate samples (red) in each group. PCA depicts complete separation of overall pattern in CR vs. Ad lib (AL) samples, (B) The genes differentially expressed (upregulated or downregulated in the CR relative to AL) are clustered according to treatment group. The color gradient (red, up-regulation; green, down-regulation) represents normalized gene expression of each gene in all of the samples listed on the right side of each row. The dendrogram on the left shows the grouping of samples based on the similarity of gene expressions amongst them. Samples were clearly grouped according to CR treatment.
Mentions: Microarray analysis was conducted to examine the global LV gene expression profile underlying the demonstrated preconditioning effect of short-term CR. The gene-expression patterns of CR and AL mice were compared using MOE 430.2 Affymetrix Gene Chip Array. A total of 6977 transcripts were significantly regulated (unpaired T-test corrected P≤0.05 false discovery rate (FDR) Benjamini-Hochberg), with 115 genes showing ≥2-fold up-or down-regulation in CR vs. AL. Both principal component analysis (PCA) and hierarchical clustering (heat maps) demonstrated clear differences in global gene expression between the two groups (Fig 3A and 3B). We also conducted quantitative PCR (qPCR) validation of several genes that were differentially regulated in the array of CR vs. AL (Fig. B in S2 File). To identify pathways and processes that were enriched with differentially regulated genes in CR vs. AL, we next conducted a GSEA (Fig 4). Pathways associated with ECM remodeling, angiogenesis, cell morphology, migration and immune response were down-regulated in CR. Interestingly, there was high enrichment in pathways associated with anti-oxidative stress, circadian rhythmicity and biological clock, which have been previously described in life-long CR studies [13, 23, 32]. Our results demonstrate that short-term CR for only 7d promotes global changes in cardiac gene expression, resembling in part what has been described in long-term CR.

Bottom Line: This short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). mRNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM).Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3ß, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1α, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38).CR regimen was also associated with reduced protein abundance of cleaved caspase 3 in the infarcted heart and improved cardiac function.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, Ontario, Canada.

ABSTRACT

Objective: To understand the molecular pathways underlying the cardiac preconditioning effect of short-term caloric restriction (CR).

Background: Lifelong CR has been suggested to reduce the incidence of cardiovascular disease through a variety of mechanisms. However, prolonged adherence to a CR life-style is difficult. Here we reveal the pathways that are modulated by short-term CR, which are associated with protection of the mouse heart from ischemia.

Methods: Male 10-12 wk old C57bl/6 mice were randomly assigned to an ad libitum (AL) diet with free access to regular chow, or CR, receiving 30% less food for 7 days (d), prior to myocardial infarction (MI) via permanent coronary ligation. At d8, the left ventricles (LV) of AL and CR mice were collected for Western blot, mRNA and microRNA (miR) analyses to identify cardioprotective gene expression signatures. In separate groups, infarct size, cardiac hemodynamics and protein abundance of caspase 3 was measured at d2 post-MI.

Results: This short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). mRNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM). Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3ß, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1α, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38). CR regimen was also associated with reduced protein abundance of cleaved caspase 3 in the infarcted heart and improved cardiac function.

No MeSH data available.


Related in: MedlinePlus