PMID- 30071860
OWN - NLM
STAT- MEDLINE
DCOM- 20190128
LR  - 20190924
IS  - 1475-2840 (Electronic)
IS  - 1475-2840 (Linking)
VI  - 17
IP  - 1
DP  - 2018 Aug 2
TI  - Regulation of diabetic cardiomyopathy by caloric restriction is mediated by 
      intracellular signaling pathways involving 'SIRT1 and PGC-1alpha'.
PG  - 111
LID - 10.1186/s12933-018-0754-4 [doi]
LID - 111
AB  - BACKGROUND: Metabolic disorders such as obesity, insulin resistance and type 2 
      diabetes mellitus (DM2) are all linked to diabetic cardiomyopathy that lead to 
      heart failure. Cardiomyopathy is initially characterized by cardiomyocyte 
      hypertrophy, followed by mitochondrial dysfunction and fibrosis, both of which 
      are aggravated by angiotensin. Caloric restriction (CR) is cardioprotective in 
      animal models of heart disease through its catabolic activity and activation of 
      the expression of adaptive genes. We hypothesized that in the diabetic heart; 
      this effect involves antioxidant defenses and is mediated by SIRT1 and the 
      transcriptional coactivator PGC-1alpha (Peroxisome proliferator-activated receptor-gamma 
      coactivator). METHODS: Obese Leptin resistant (db/db) mice characterized by DM2 
      were treated with angiotensin II (AT) for 4 weeks to enhance the development of 
      cardiomyopathy. Mice were concomitantly either on a CR diet or fed ad libitum. 
      Cardiomyocytes were exposed to high levels of glucose and were treated with 
      EX-527 (SIRT1 inhibitor). Cardiac structure and function, gene and protein 
      expression and oxidative stress parameters were analyzed. RESULTS: AT treated 
      db/db mice developed cardiomyopathy manifested by elevated levels of serum 
      glucose, cholesterol and cardiac hypertrophy. Leukocyte infiltration, fibrosis 
      and an increase in an inflammatory marker (TNFalpha) and natriuretic peptides (ANP, 
      BNP) gene expression were also observed. Oxidative stress was manifested by low 
      SOD and PGC-1alpha levels and an increase in ROS and MDA. DM2 resulted in ERK1/2 
      activation. CR attenuated all these deleterious perturbations and prevented the 
      development of cardiomyopathy. ERK1/2 phosphorylation was reduced in CR mice 
      (p = 0.008). Concomitantly CR prevented the reduction in SIRT activity and PGC-1alpha 
      (p < 0.04). Inhibition of SIRT1 activity in cardiomyocytes led to a marked 
      reduction in both SIRT1 and PGC-1alpha. ROS levels were significantly (p < 0.03) 
      increased by glucose and SIRT1 inhibition. CONCLUSION: In the current study we 
      present evidence of the cardioprotective effects of CR operating through SIRT1 
      and PGC-1 alpha, thereby decreasing oxidative stress, fibrosis and inflammation. Our 
      results suggest that increasing SIRT1 and PGC-1alpha levels offer new therapeutic 
      approaches for the protection of the diabetic heart.
FAU - Waldman, Maayan
AU  - Waldman M
AD  - Cardiac Research Laboratory, Felsenstein Medical Research Institute Petah-Tikva, 
      Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
AD  - Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of 
      Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Cohen, Keren
AU  - Cohen K
AD  - Cardiac Research Laboratory, Felsenstein Medical Research Institute Petah-Tikva, 
      Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
AD  - Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of 
      Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Yadin, Dor
AU  - Yadin D
AD  - Cardiac Research Laboratory, Felsenstein Medical Research Institute Petah-Tikva, 
      Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
AD  - Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of 
      Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Nudelman, Vadim
AU  - Nudelman V
AD  - Cardiac Research Laboratory, Felsenstein Medical Research Institute Petah-Tikva, 
      Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Gorfil, Dan
AU  - Gorfil D
AD  - Cardiac Research Laboratory, Felsenstein Medical Research Institute Petah-Tikva, 
      Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Laniado-Schwartzman, Michal
AU  - Laniado-Schwartzman M
AD  - Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA.
FAU - Kornwoski, Ran
AU  - Kornwoski R
AD  - Cardiac Research Laboratory, Felsenstein Medical Research Institute Petah-Tikva, 
      Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Aravot, Dan
AU  - Aravot D
AD  - Cardiac Research Laboratory, Felsenstein Medical Research Institute Petah-Tikva, 
      Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Abraham, Nader G
AU  - Abraham NG
AD  - Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA.
FAU - Arad, Michael
AU  - Arad M
AD  - Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of 
      Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Hochhauser, Edith
AU  - Hochhauser E
AD  - Cardiac Research Laboratory, Felsenstein Medical Research Institute Petah-Tikva, 
      Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 
      hochhaus@post.tau.ac.il.
AD  - Felsenstein Research Center, Rabin Medical Center, Sackler Faculty of Medicine, 
      Tel Aviv University, Jabotinsky St, 49100, Petach Tikva, Israel. 
      hochhaus@post.tau.ac.il.
LA  - eng
GR  - R01 HL139793/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20180802
PL  - England
TA  - Cardiovasc Diabetol
JT  - Cardiovascular diabetology
JID - 101147637
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (Ppargc1a protein, rat)
RN  - 11128-99-7 (Angiotensin II)
RN  - EC 3.5.1.- (Sirt1 protein, mouse)
RN  - EC 3.5.1.- (Sirt1 protein, rat)
RN  - EC 3.5.1.- (Sirtuin 1)
SB  - IM
EIN - Cardiovasc Diabetol. 2018 Aug 17;17(1):115. PMID: 30119667
MH  - Angiotensin II
MH  - Animals
MH  - *Caloric Restriction
MH  - Cells, Cultured
MH  - Diabetes Mellitus, Type 2/*diet therapy/enzymology/etiology/physiopathology
MH  - Diabetic Cardiomyopathies/enzymology/etiology/physiopathology/*prevention & 
      control
MH  - Disease Models, Animal
MH  - Fibrosis
MH  - Hypertension/chemically induced
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Myocardium/*enzymology/pathology
MH  - Obesity/complications
MH  - Oxidative Stress
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 
      1-alpha/genetics/*metabolism
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
MH  - Sirtuin 1/*metabolism
MH  - Ventricular Remodeling
PMC - PMC6090985
OTO - NOTNLM
OT  - Caloric restriction
OT  - Cardiomyopathy
OT  - Diabetes mellitus
OT  - PGC-1alpha
OT  - SIRT1
EDAT- 2018/08/04 06:00
MHDA- 2019/01/29 06:00
PMCR- 2018/08/02
CRDT- 2018/08/04 06:00
PHST- 2018/05/17 00:00 [received]
PHST- 2018/07/26 00:00 [accepted]
PHST- 2018/08/04 06:00 [entrez]
PHST- 2018/08/04 06:00 [pubmed]
PHST- 2019/01/29 06:00 [medline]
PHST- 2018/08/02 00:00 [pmc-release]
AID - 10.1186/s12933-018-0754-4 [pii]
AID - 754 [pii]
AID - 10.1186/s12933-018-0754-4 [doi]
PST - epublish
SO  - Cardiovasc Diabetol. 2018 Aug 2;17(1):111. doi: 10.1186/s12933-018-0754-4.