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Increased TGFβ Signaling in Hearts of Type I Diabetic Mice May Result in Diabetic Cardiac Autonomic Dysfunction
Author(s) -
Georgescu Serban Paul,
Naggar Jack,
Aronovitz Mark,
Welzig Charles Michael,
Picard Kristen,
Vaikus Celestia,
Zhang Yali,
Park Ho-Jin,
Karas Richard,
Galper Jonas B.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1057.8
Subject(s) - medicine , endocrinology , bradycardia , chronotropic , heart rate , blood pressure
Diabetic Autonomic Neuropathy (DAN), a complication of diabetes is associated with cardiac parasympathetic dysfunction, severe arrhythmias and sudden death. Increased TGFβ signaling has been implicated in the mechanism of end organ damage in type I diabetes. We had shown that in atrial myocytes TGFβ attenuates the negative chronotropic response of the heart to the acetylcholine analogue Carbamylcholine (Carb). To determine whether TGFβ signaling was increased in the diabetic heart we compared PAI‐1 and TGFβRII levels in atria of Akita Type I diabetic mice (DM) and WT mice. PAI‐1 mRNA determined by qPCR increased 1.6±0.33 fold, n=4 p<0.03. Western blots demonstrated increased pSmad2/3 and a 3.4±0.5fold, n=3 p<0.03 increase in the TGFβRII. Treatment of mice with insulin pellets reversed these effects. Using EKG transmitters we compared carb‐induced bradycardia in WT and DM. Duration of bradycardia was 5.1 min in DM vs 12.6 min in WT. SB‐505124 (SB, an inhibitor of TGFβ signaling) treatment for 10d restored the level of PAI‐1 mRNA in the DM to WT levels, increased duration of bradycardia in response to carb to 11.1 min. In whole cell patch clamp studies of Akita atrial myocytes SB increased IKAch, the K current which mediates the decrease in heart rate to levels similar to those in WT cells: −248±15 pA/pF to 341±15 pA/pF n=15, p<0.01. Thus elevated TGFβ signaling in type I diabetic mouse appears to be associated with cardiac DAN.