The Physiological Effects of the Non-Neuronal Cardiac Cholinergic System on the Heart and Extra-Cardiac Organs
Keywords:
Acetylcholine (ACh), Non-neuronal cardiac cholinergic system (NNCCS), Heart, Oxygen consumption, Energy metabolism, Angiogenesis, Gap junction, Anti-ischemia/hypoxia, Blood brain barrier, Anti-inflammationAbstract
It has been independently reported that cardiomyocytes possess a system to synthesize acetylcholine (Ach), which is called nonneuronal ACh, and therefore, this system in the heart is named the non-neuronal cardiac cholinergic system (NNCCS). This system is involved in many cardiac physiological aspects including cardiac homeostasis, for example, negative regulation of oxygen consumption, enhancement of glucose preference as a cardiac energy substrate, acceleration of angiogenesis, and upregulation of gap junction function, etc., in other words, enhancement of resilience against damages by ischemia or hypoxia in the heart. The history of the establishment of the NNCCS concept, significant findings of NNCCS functions, the pathogenic roles in the impairment of NNCCS, the link between NNCCS and extra-cardiac organs through the vagal nerve, and its influences on extra-cardiac organ functions are provided in this review.
References
Fujii T, Kawashima K, 2001, The Non-Neuronal Cholinergic System: An Independent Non-Neuronal Cholinergic System in Lymphocytes. Jpn J Pharmacol, 85(1): 11–15.
Kummer W, Lips KS, Pfeil U, 2008, The Epithelial Cholinergic System of the Airways. Histochem Cell Biol, 130(2): 219–234.
Wilson C, Lee MD, McCarron JG, Acetylcholine Released by Endothelial Cells Facilitates Flow-Mediated Dilatation. J Physiol, 594: 7267–7307.
Kakinuma Y, Akiyama T, Sato T, 2009. Cholinoceptive and Cholinergic Properties of Cardiomyocytes Involving an Amplification Mechanism for Vagal Efferent Effects in Sparsely Innervated Ventricular Myocardium. FEBS J, 276(18): 5111–5125.
Hoover DB, Ganote CE, Ferguson SM, et al., 2004, Localization of Cholinergic Innervation in Guinea Pig Heart by Immunohistochemistry for High-Affinity Choline Transporters. Cardiovasc Res, 62(1): 112–121.
Rana OR, Schauerte P, Kluttig R, et al., 2010, Acetylcholine as an Age-Dependent Non-Neuronal Source in the Heart. Auton Neurosci, 156: 82–89.
Rocha-Resende C, Roy A, Resende R, et al., 2012, Non-Neuronal Cholinergic Machinery Present in Cardiomyocytes Offsets Hypertrophic Signals. J Mol Cell Cardiol, 53: 206–216.
Roy A, Fields WC, Rocha-Resende C, et al., 2013, Cardiomyocyte-Secreted Acetylcholine is Required for Maintenance of Homeostasis in the Heart. FASEB J, 27: 5072–5082.
Kakinuma Y, Furihata M, Akiyama T, et al., 2010, Donepezil, and Acetylcholinesterase Inhibitor Against Alzheimer’s Dementia, Promotes Angiogenesis in an Ischemic Hindlimb Model. J Mol Cell Cardiol, 48(4): 680–693.
Kakinuma Y, Akiyama T, Okazaki K, et al., 2012, A Non-Neuronal Cardiac Cholinergic System Plays a Protective Role in Myocardium Salvage during Ischemic Insults. PLoS One, 7(11): e50761.
Oikawa S, Kai Y, Mano A, et al., 2021, Non-Neuronal Cardiac Acetylcholine System Playing Indispensable Roles in Cardiac Homeostasis Confers Resiliency to the Heart. J Physiol Sci, 71(1): 2.
Palatini P, Benetos A, Julius S, 2006, Impact of Increased Heart Rate on Clinical Outcomes in Hypertension: Implications for Antihypertensive Drug Therapy. Drugs, 66(22): 133–144.
Kakinuma Y, Ando M, Kuwabara M, et al., 2005, Acetylcholine from Vagal Stimulation Protects Cardiomyocytes Against Ischemia and Hypoxia Involving Additive Non-Hypoxic Induction of HIF-1α. FEBS Lett 579(10): 2111–2118.
Oikawa S, Iketani M, Kakinuma Y, 2014, A Non-Neuronal Cholinergic System Regulates Cellular ATP Levels to Maintain Cell Viability. Cell Physiol Biochem, 34(3): 781–789.
Kakinuma Y, Tsuda M, Okazaki K, et al., 2013, Heart-Specific Overexpression of Choline Acetyltransferase Gene Protects Murine Heart Against Ischemia Through Hypoxia-Inducible Factor-1α-Related Defense Mechanisms. J Am Heart Assoc, 2(1): e004887.
Oikawa S, Kai Y, Tsuda M, et al., 2016, Non-Neuronal Cardiac Cholinergic System Influences CNS via the Vagus Nerve to Acquire a Stress-Refractory Propensity. Clin Sci (Lond), 130(21): 1913–1928.
Oikawa S, Kai Y, Mano A, et al., 2019, Potentiating a Non-Neuronal Cardiac Cholinergic System Reinforces the Functional Integrity of the Blood Brain Barrier Associated with Systemic Anti-Inflammatory Responses. Brain Behav Immun, 81: 122–137.
Echeverria V, Yarkov A, Aliev G, 2016, Positive Modulators of the α7 Nicotinic Receptor Against Neuroinflammation and Cognitive Impairment in Alzheiner’s Disease. Prog Neurobiol, 144: 142–157.
Wang H, Yu M, Ochani M, et al., 2003, Nicotinic Acetylcholine Receptor Alpha7 Subunit is an Essential Regulator of Inflammation. Nature, 421: 384–388.
Nordström P, Religa D, Wimo A, et al., 2013, The Use of Cholinesterase Inhibitors and the Risk of Myocardial Infarction and Death: a Nationwide Cohort Study in Subjects with Alzheimer’s Disease. Eur Heart J, 34(33): 2585–2591.
Wu PH, Lin YT, Hsu PC, et al., 2015, Impact of Acetylcholinesterase Inhibitors on the Occurrence of Acute Coronary Syndrome in Patients with Dementia. Sci Rep, 5: 15451.
Saw EL, Pearson JT, Schwenke DO, et al., Activation of the Cardiac Non-Neuronal Cholinergic System Prevents the Development of Diabetes-Associated Cardiovascular Complications. Cardiovasc Diabetol, 20: 50.
