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Methods for the Isolation, Culture, and Functional Characterization of Sinoatrial Node Myocytes from Adult Mice
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Depressed HCN4 function in the type 2 diabetic sinoatrial node

Sajida Parveen1, Paddy H S Cheah1, Luke P I Worthington1

  • 1Department of Physiology, School of Biomedical Sciences, and HeartOtago, University of Otago, Dunedin, Otago, New Zealand.

Molecular and Cellular Biochemistry
|December 27, 2022
PubMed

Insights

Type 2 diabetes impairs heart rate control by reducing HCN4 channel expression and function in the sinoatrial node. This study reveals key mechanisms behind diabetic bradycardia.

Area of Science:

  • Cardiovascular Physiology
  • Diabetology
  • Molecular Cardiology

Background:

  • Type 2 diabetes mellitus (T2DM) is associated with impaired autonomic control of heart rate (HR).
  • Intrinsic HR generation within the sinoatrial node (SAN) may be affected in T2DM, as suggested by previous findings of lower ex vivo HR in diabetic rat hearts.
  • Hyperpolarisation-activated cyclic nucleotide-gated 4 (HCN4) channels are critical for pacemaking in the SAN.

Purpose of the Study:

  • To investigate if reduced intrinsic HR in type 2 diabetic hearts is caused by alterations in HCN4 channel function, protein expression, or distribution.
  • To elucidate the molecular mechanisms underlying impaired cardiac chronotropy in T2DM.

Main Methods:

  • Isolated Langendorff-perfused hearts from Zucker type 2 Diabetic Fatty (ZDF) rats (DM) and non-diabetic littermates (nDM) were used.
  • Intrinsic HR response to HCN4 channel blockade with ivabradine was assessed.
  • HCN4 protein expression and membrane localization in the SAN were analyzed using western blot and immunofluorescence.

Main Results:

  • Intrinsic HR was significantly lower in DM hearts compared to nDM hearts.
  • The response to ivabradine was diminished in DM hearts, normalizing HR between groups.
  • HCN4 protein expression was decreased in the SAN of DM rats, with no change in membrane localization.

Conclusions:

  • Lower intrinsic HR in type 2 diabetic hearts is likely due to decreased HCN4 expression and impaired HCN4 channel function.
  • This study provides novel insights into the intrinsic mechanisms of altered HR regulation in T2DM.
  • Findings highlight HCN4 channels as a potential therapeutic target for diabetic cardiac dysfunction.

Keywords:
Heart rateSinoatrial nodeType 2 diabetes

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