Premium
Increased TGFb signaling in type I diabetic mice is associated with parasympathetic dysfunction of the heart
Author(s) -
Georgescu Serban,
Naggar Jack C,
Welzig Michael C,
Zhang Yali,
Park HoJin,
Wooten Eric C,
Aronovitz Mark J,
Karas Richard H,
Huggins Gordon S,
Galper Jonas B
Publication year - 2009
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.23.1_supplement.524.14
Subject(s) - medicine , endocrinology , chronotropic , stimulation , diabetic cardiomyopathy , downregulation and upregulation , bradycardia , muscarinic acetylcholine receptor , diabetes mellitus , receptor , heart failure , heart rate , biology , cardiomyopathy , biochemistry , blood pressure , gene
Diabetic Autonomic Neuropathy (DAN), a severe complication of diabetes, is associated with parasympathetic dysfunction, severe arrhythmias and sudden death. We had shown in cardiac myocytes that TGFb attenuates the negative chronotropic response to Carbamylcholine and decreases the expression of M2 muscarinic receptor and Gai2 (components of the cardiac parasympathetic response). Increased TGFb signaling has been implicated in the end organ damage mechanisms in patients and in type I diabetic animal models. Our hypothesis: the decreased response of the diabetic heart to parasympathetic stimulation might be due to increased TGFb signaling. Here we present a new animal model for DAN. Compared to WT, Akita type I diabetic mice showed a decreased Carbamylcholine‐induced bradycardia and a faster recovery to 80% of initial heart rate. Compared to WT, the diabetic heart showed significant increases in mRNA expression of TGFbRII and PAI‐1 (a target of TGFb signaling). Western blots using hearts lysates showed increased phospho‐Smad2/3 and TGFbRII levels in Akita mice. Together with our previous data that TGFb stimulation attenuates the parasympathetic response in cardiac myocytes, these in vivo results suggest that in type I diabetic mice elevated TGFb signaling is associated with parasympathetic dysfunction of the heart, and that TGFb may be involved in the arrhythmia mechanisms in the diabetic heart.