Advanced glycation endproduct (AGE) accumulation and AGE receptor (RAGE) up-regulation contribute to the onset of diabetic cardiomyopathy

Heng Ma, Shi Yan Li, Peisheng Xu, Sara A. Babcock, E. Kurt Dolence, Michael Brownlee, Ji Li, Jun Ren

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

Diabetic cardiomyopathy is manifested by compromised systolic and diastolic function. This study was designed to examine the role of advanced glycation endproduct (AGE) and AGE receptor (RAGE) in diabetic cardiomyopathy. Heart function was assessed in isolated control and streptozotocin-induced diabetic hearts following in vivo RAGE gene knockdown using RNA interference. Cardiomyocyte mechanical properties were evaluated including peak shortening (PS), time-to-PS (TPS) and time-to-90% relengthening (TR90). RAGE was assayed by RT-PCR and immunoblot. Diabetes significantly enhanced cardiac MG, AGE and RAGE levels accompanied with colocalization of AGE and RAGE in cardiomyocytes. Diabetes-elicited increase in RAGE was inhibited by in vivo siRNA interference. The AGE formation inhibitor benfotiamine significantly attenuated diabetes-induced elevation in MG, AGE, RAGE and collagen cross-linking without affecting hypertriglyceridaemia and hypercholesterolaemia in diabetes. Diabetes markedly decreased LV contractility, as evidenced by reduced ±dP/dt and LV developed pressure (LVDP), which were protected by RAGE gene knockdown. In addition, MG-derived AGE (MG-AGE) up-regulated cardiac RAGE mRNA and triggered cardiomyocyte contractile dysfunction reminiscent of diabetic cardiomyopathy. The MG-AGE-elicited prolongation of TPS and TR 90 was ablated by an anti-RAGE antibody in cardiomyocytes. Interestingly, MG-AGE-induced cardiomyocyte dysfunction was associated with mitochondrial membrane potential (MMP) depolarization and reduced GSK-3β inactivation in control cardiomyocytes, similar to those from in vivo diabetes. Treatment with siRNA-RAGE ablated diabetes-induced MMP depolarization and GSK-3β inactivation. Collectively, our result implicated a role of AGE-RAGE in the pathogenesis of diabetic cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)1751-1764
Number of pages14
JournalJournal of Cellular and Molecular Medicine
Volume13
Issue number8 B
DOIs
StatePublished - Aug 1 2009

Keywords

  • Advanced glycation endproduct (AGE)
  • Cardiac
  • Diabetes
  • RAGE
  • SiRNA

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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