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cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart

Lee B Bockus1, Kenneth M Humphries2

  • 1From the Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 and the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.

The Journal of Biological Chemistry
|October 16, 2015
PubMed

Insights

Diabetes impairs heart function by disrupting cAMP-dependent protein kinase (PKA) signaling, leading to reduced cardiac responses. Addressing high lipid levels may restore cardiac signaling and function in diabetic patients.

Area of Science:

  • Cardiovascular Physiology
  • Metabolic Disorders
  • Molecular Signaling

Background:

  • Diabetes mellitus is linked to cardiac dysfunction and heart failure.
  • Autonomic control of heart function involves cAMP-dependent protein kinase (PKA) signaling.
  • Diabetic hearts exhibit reduced β-adrenergic responsiveness, with unclear effects on PKA signaling.

Purpose of the Study:

  • To investigate the direct impact of diabetes on PKA signaling pathways in the heart.
  • To determine if receptor-independent PKA activation can reveal post-receptor defects in diabetic cardiac function.

Main Methods:

  • Utilized streptozotocin-induced diabetic mice and control littermates.
  • Administered 8-bromo-cAMP (8Br-cAMP) to activate PKA directly.
  • Evaluated cardiac hemodynamic function and PKA signaling pathway components (activity, catalytic subunit content, substrate phosphorylation).
  • Assessed PKA signaling in adult cardiomyocytes cultured with lipid supplementation.

Main Results:

  • Diabetic mice showed impaired inotropic and lusitropic responses to 8Br-cAMP, indicating post-receptor defects.
  • Reduced PKA activity and catalytic subunit levels were observed in diabetic hearts.
  • Compartment-specific PKA loss correlated with decreased substrate phosphorylation, including the glycolytic activator PFK-2.
  • Cultured cardiomyocytes exposed to lipids mimicked diabetic PKA signaling deficits.

Conclusions:

  • PKA signaling is significantly impaired in the diabetic heart.
  • Diabetes-induced cardiac dysfunction involves post-receptor defects in PKA signaling.
  • Lipotoxicity may contribute to impaired β-adrenergic signaling in diabetes, highlighting the importance of managing hyperlipidemia.

Keywords:
cardiac metabolismcardiomyocytediabetesheartprotein kinase A (PKA)

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