Temporal dystrophic remodeling within the intrinsic cardiac nervous system of the streptozotocin-induced diabetic rat model

Abstract

IntroductionThe pathogenesis of heart failure (HF) in diabetic individuals, called “diabetic cardiomyopathy”, is only partially understood. Alterations in the cardiac autonomic nervous system due to oxidative stress have been implicated. The intrinsic cardiac nervous system (ICNS) is an important regulatory pathway of cardiac autonomic function, however, little is known about the alterations that occur in the ICNS in diabetes. We sought to characterize morphologic changes and the role of oxidative stress within the ICNS of diabetic hearts. Cultured ICNS neuronal cells from the hearts of 3- and 6-month old type 1 diabetic streptozotocin (STZ)-induced diabetic Sprague-Dawley rats and age-matched controls were examined. Confocal microscopy analysis for protein gene product 9.5 (PGP 9.5) and amino acid adducts of (E)-4-hydroxy-2-nonenal (4-HNE) using immunofluorescence was undertaken. Cell morphology was then analyzed in a blinded fashion for features of neuronal dystrophy and the presence of 4-HNE adducts.ResultsAt 3-months, diabetic ICNS neuronal cells exhibited 30% more neurite swellings per area (p = 0.01), and had a higher proportion with dystrophic appearance (88.1% vs. 50.5%; p = <0.0001), as compared to control neurons. At 6-months, diabetic ICNS neurons exhibited more features of dystrophy as compared to controls (74.3% vs. 62.2%; p = 0.0448), with 50% more neurite branching (p = 0.0015) and 50% less neurite outgrowth (p = <0.001). Analysis of 4-HNE adducts in ICNS neurons of 6-month diabetic rats demonstrated twice the amount of reactive oxygen species (ROS) as compared to controls (p = <0.001).ConclusionNeuronal dystrophy occurs in the ICNS neurons of STZ-induced diabetic rats, and accumulates temporally within the disease process. In addition, findings implicate an increase in ROS within the neuronal processes of ICNS neurons of diabetic rats suggesting an association between oxidative stress and the development of dystrophy in cardiac autonomic neurons.

Chronic intermittent hypoxia remodels catecholaminergic nerve innervation in mouse atria

“…Following CIH exposure, we observed a clustering of ICG neurons because they were more crowded compared to RA. This observation is consistent with ICG remodelling in CIH (Lin et al, 2008) as well as in Goto-Kakizaki and streptozotocin-induced diabetic rats and mice (Batulevicius et al, 2013;Lin et al, 2010;Menard et al, 2014). Thus, an association between ICG remodelling and pathological conditions may be present and deserves further exploration.…”

Cardiac surgery elicits pericardial inflammatory responses that are distinct compared with postcardiopulmonary bypass systemic inflammation

“…Many complications associated with cardiac surgery, such as POAF, postsurgical pericardial adhesions, and PPS are driven by inflammation. 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 Although there is also evidence to suggest that systemic factors and physiological parameters such as heart rate variability can contribute to atrial fibrillation, 8 , 27 , 28 , 29 , 30 , 31 a better understanding of the inflammatory processes that take place in the pericardial space after surgery may explain the precise mechanisms that drive POAF, postsurgical pericardial adhesion formation, and PPS. Within the first 48 hours after CABG surgery, compared with blood, the pericardial space is populated by significantly higher concentrations of potent proinflammatory and anti-inflammatory mediators, such as IL-6 and TGFβ, respectively.…”

The Intrinsic Cardiac Nervous System: From Pathophysiology to Therapeutic Implications

“…These data remain currently one of a kind. More recently, in the attempt to unravel potentially specific ICNS-related neuronal mechanisms underlying the pathophysiology of diabetic cardiomyopathy and HF, Menard et al [141] assessed the impact of diabetes on ICNS. They showed a temporal dystrophic remodeling affecting ICNS associated with the accumulation of reactive oxygen species (ROS) as compared to controls.…”