Cardiovascular diseases are the leading cause of mortality and morbidity and many of the cardiovascular disorders (hypertension, cardiomyopathy, decreased cardiac reflexes, and cardiac failure) are intimately associated with aging, sleep apnea (intermittent hypoxia), and diabetes mellitus. Among these disorders, the reduction of autonomic control of the heart rate in patients is very dangerous and it is commonly used as a risk predictor for life threatening arrhythmia which causes sudden death. However, the neural mechanisms involved in cardiac neuropathy of aging, intermittent hypoxia, and diabetes-related cardiovascular morbidity, are poorly understood. More specifically, precise physiological and anatomical assessments of reductions in autonomic control of the cardiovascular function and the underlying morphological reorganization of cardiac circuitry during aging, following intermittent hypoxia (sleep apnea), in chronic diabetes are currently poorly defined due to past technical limitations. Detailed characterization of the organization and reorganization of autonomic axons and terminals in cardiac tissues is an essential component towards increasing our understanding of aging-, chronic intermittent hypoxia-, and diabetes- related cardiac processes. The long-term goal of my research is first to study modifications of the cardiac functions and the changes of the neural circuitry in the brain-heart axis of aged, intermittent hypoxia-exposed, and diabetes in rat and mouse models at different ages (young, mid-age, and old) as well as to characterize cardiac nerve regeneration after denervation. Then, we will seek for medical interventions to prevent/reduce such pathological changes as well as to promote cardiac nerve regeneration.
We will use the recent technological advances in my lab and my collaborators’ labs to test our leading hypothesis that functional changes, morphological reorganization, and enhanced ROS production of the parasympathetic nervous system occur at multiple sites within the brain-heart axis in intermittent hypoxia-exposed and chronic diabetic animals. Since advanced age is a strong risk factor for neuropathy, we further hypothesize that aging and diabetes/sleep apnea may interact to exacerbate deleterious processes.
Technically, we have first successfully developed a combination of novel anatomical techniques, including microinjections, anterograde tracing, laser scanning confocal microscopy, and stereological counting strategies to qualitatively and quantitatively characterize vagal cardiac axons and terminals in rat hearts. Second, we have established a selective lesion protocol to dissect the functional roles of nucleus ambiguus (NA) and the dorsal motor nucleus of the vagus (DmnX). Thirdly, we have obtained a unique transgenic mouse model of chronic type 1 diabetes (OVE26), thereby permitting detailed examination of functional and anatomical alterations in the chronic diabetic heart. Fourth, we have used a rather unique rodent model of intermittent hypoxia that closely mimics the behavioral, anatomical, and physiological consequences of obstructive sleep apnea. Therefore, we are able to examine the functional and anatomical alterations in chemoreceptor and baroreceptor reflexes. Finally, we have established two physiological systems which will allow us to record aortic nerve activity in vivo and to patch-clamp baroreceptor neurons in the nodose ganglion of rats.
1: Cheng ZJ. Vagal cardiac efferent innervation in F344 rats: Effects of chronic
intermittent hypoxia. Auton Neurosci. 2016 Oct 29. pii: S1566-0702(16)30236-3.
doi: 10.1016/j.autneu.2016.10.005. [Epub ahead of print] PubMed PMID: 27839717.
2: Hatcher J, Gu H, Cheng ZJ. SOD1 Overexpression Preserves Baroreflex Control of
Heart Rate with an Increase of Aortic Depressor Nerve Function. Oxid Med Cell
Longev. 2016;2016:3686829. doi: 10.1155/2016/3686829. PubMed PMID: 26823951;
PubMed Central PMCID: PMC4707341.
3: Harris DM, Bellew C, Cheng ZJ, Cendán JC, Kibble JD. High-fidelity patient
simulators to expose undergraduate students to the clinical relevance of
physiology concepts. Adv Physiol Educ. 2014 Dec;38(4):372-5. doi:
10.1152/advan.00063.2014. PubMed PMID: 25434023.
4: Li L, Hatcher JT, Hoover DB, Gu H, Wurster RD, Cheng ZJ. Distribution and
morphology of calcitonin gene-related peptide and substance P immunoreactive
axons in the whole-mount atria of mice. Auton Neurosci. 2014 Apr;181:37-48. doi:
10.1016/j.autneu.2013.12.010. PubMed PMID: 24433968.
- Gui L, Bao Z, Jia Y, Qin X, Cheng ZJ, Zhu J, Chen QH. Ventricular
tachyarrhythmias in rats with acute myocardial infarction involves activation of
small-conductance Ca2+-activated K+ channels. Am J Physiol Heart Circ Physiol.
2013 Jan 1;304(1):H118-30. doi: 10.1152/ajpheart.00820.2011. PubMed PMID:
6: Dayyat EA, Zhang SX, Wang Y, Cheng ZJ, Gozal D. Exogenous erythropoietin
administration attenuates intermittent hypoxia-induced cognitive deficits in a
murine model of sleep apnea. BMC Neurosci. 2012 Jul 3;13:77. doi:
10.1186/1471-2202-13-77. PubMed PMID: 22759774; PubMed Central PMCID: PMC3412695.
7: Lin M, Hatcher JT, Wurster RD, Chen QH, Cheng ZJ. Characteristics of single
large-conductance Ca2+-activated K+ channels and their regulation of action
potentials and excitability in parasympathetic cardiac motoneurons in the nucleus
ambiguus. Am J Physiol Cell Physiol. 2014 Jan 15;306(2):C152-66. doi:
10.1152/ajpcell.00423.2012. PubMed PMID: 24196530; PubMed Central PMCID:
8: Lin M, Hatcher JT, Chen QH, Wurster RD, Li L, Cheng ZJ. Maternal diabetes
increases large conductance Ca2+-activated K+ outward currents that alter action
potential properties but do not contribute to attenuated excitability of
parasympathetic cardiac motoneurons in the nucleus ambiguus of neonatal mice. Am
J Physiol Regul Integr Comp Physiol. 2011 May;300(5):R1070-8. doi:
10.1152/ajpregu.00470.2010. PubMed PMID: 21248308; PubMed Central PMCID:
9: Lin M, Hatcher JT, Chen QH, Wurster RD, Cheng ZJ. Small conductance
Ca2+-activated K+ channels regulate firing properties and excitability in
parasympathetic cardiac motoneurons in the nucleus ambiguus. Am J Physiol Cell
Physiol. 2010 Dec;299(6):C1285-98. doi: 10.1152/ajpcell.00134.2010. PubMed PMID:
20739619; PubMed Central PMCID: PMC3774095.
10: Lin M, Chen QH, Wurster RD, Hatcher JT, Liu YQ, Li L, Harden SW, Cheng ZJ.
Maternal diabetes increases small conductance Ca2+-activated K+ (SK) currents
that alter action potential properties and excitability of cardiac motoneurons in
the nucleus ambiguus. J Neurophysiol. 2010 Oct;104(4):2125-38. doi:
10.1152/jn.00671.2009. PubMed PMID: 20668269; PubMed Central PMCID: PMC2957455.