Abstract 934: Nerve Growth Factor is Critical for Cardiac Sensory Innervation and Rescues Neuropathy in Diabetic Hearts
Background Molecular mechanisms regulating the cardiac sensory nervous system remain poorly understood. Cardiac sensory nerve impairment causes silent myocardial ischemia, the main cause of sudden death in diabetes mellitus (DM). The present study focused on the roles of nerve growth factor (NGF) in the regulation of the cardiac sensory nervous system and analyzed the mechanism of silent myocardial ischemia in DM.
Methods and Results (1) We screened neurotrophic factors, and found that cardiac sensory nerves develop sequentially after birth in parallel with NGF synthesized in the heart. (2) In NGF-deficient mice, the cardiac sensory nervous system, composed of cardiac nociceptive sensory nerves immunopositive for calcitonin gene-related peptide (CGRP), dorsal root ganglia (DRG) and dorsal horn, was markedly retarded. (3) Transgenic mice over-expressing NGF under a control of α-MHC promoter (NGFTG) were used to rescue NGF defects in NGF−/− mice (NGF−/− /TG) hearts. A strong NGF expression of 22 fold was detected in NGF−/− /TG hearts compared with NGF+/+, and NGF−/− /TG mice demonstrated complete restoration of cardiac sensory deficits. (4) DM was induced by an intraperitoneal injection of streptozotocin in wild-type and NGFTG mice. Both wild-type and NGFTG mice had similar hyperglycemia, and had lost body weight at 16 weeks. NGF mRNA expression in the heart was significantly down-regulated by 48% in DM-induced wild-type mice, and cardiac sensory denervation and atrophic changes in DRG were observed. (5) In contrast, a strong NGF expression was detected in DM-induced NGFTG hearts, and the sensory deterioration was completely rescued. (6) To analyze cardiac sensory function, the mice were subjected to myocardial ischemia and c-Fos expression in DRG, a marker of pain perception, was measured. Myocardial ischemia induced c-Fos expression in DRG, which was down-regulated by DM to 50% in the wild-type mice. (7) In contrast, DM-induced NGF transgenic mice did not show down-regulation of c-Fos induction in myocardial ischemia.
Conclusions These findings demonstrate that the development and regulation of the cardiac sensory nervous system are dependent on NGF synthesized in the heart, and that DM-induced NGF reduction causes cardiac sensory neuropathy.