Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease

Abstract

The nervous system and cardiovascular system develop in concert and are functionally interconnected in both health and disease. This white paper focuses on the cellular and molecular mechanisms that underlie neural-cardiac interactions during development, during normal physiological function in the mature system, and during pathological remodelling in cardiovascular disease. The content on each subject was contributed by experts, and we hope that this will provide a useful resource for newcomers to neurocardiology as well as aficionados.

Figure 1. Schematic representation of the neuromodulatory pathways influencing the release of noradrenaline (NA) and acetylcholine (ACh) from postganglionic sympathetic and parasympathetic neurons

Neuromodulators can arise from the coronary microvasculature (e.g. angiotensin II (AT II) and C‐type natriuretic peptide (CNP)), myocytes (B‐type natriuretic peptide (BNP)) as well as between neurons (neuropeptide Y (NPY), galanin (Gal), acetylcholine (ACh) and vasoactive intestinal peptide (VIP)) and within neurons (such as neuronal nitric oxide synthase (nNOS) and its activator protein, CAPON). Stimulatory pathways are represented by green arrows, and inhibitory pathways by red arrows. β, beta adrenergic receptor; M, muscarinic receptor.

Figure 2. Diagram of the pathophysiological interactions between the cardiac sensory nerves and diseased state

CGRP can cause activation of multiple signalling pathways and has cardioprotective effects. Cardiovascular disease and autonomic neuropathy can lead to downregulation of CGRP, which causes inflammation, vasoconstriction, impairing angiogenesis, fibrosis and apoptosis, and may ultimately lead to heart failure or sudden cardiac death. CGRP, calcitonin gene‐related peptide; ROS, reactive oxygen species; PI3K, phosphatidylinositol‐3 kinase; Akt, serine/threonine‐specific protein kinase; ERK, extracellular signal‐regulated kinases; Bcl‐2/Bax, B‐cell lymphoma 2/Bcl‐2‐associated X protein.

Figure 3. Crosstalk between cardiomyocyte and sympathetic nerve via humoral factors in diseased heart

Failing cardiomyocytes induce NGF via an endothelin‐1 mediated pathway and LIF. NGF leads to hyperinnervation (anatomical modulation) and LIF leads to rejuvenation/cholinergic differentiation (functional modulation). This phenomenon shows the expression of catecholaminergic marker such as reduced TH and increased cholinergic (CHT, ChAT) and juvenile markers (PSA‐NCAM). PSA‐NCAM, polysialylated neural cell adhesion molecule; TrkA, tropomyosin‐related kinase A; NGF, nerve growth factor; LIF, leukemia inhibitory factor; LIFR, LIF receptor; TH, tyrosine hydroxylase.

Figure 4. Neurohumoral activation of CaMKII

Catecholamines, angiotensin II and aldosterone are upstream activators of CaMKII by inducing post‐translational modifications (PTM) to the N‐terminus of the regulatory domain (blue horizontal bar, see text). Catecholamine agonists promote phosphorylation of threonine 287 and nitrosylation of cysteine 290. Angiotensin II and aldosterone increase oxidant stress leading to oxidation of methionines 281 and 282. Hyperglycaemia can also activate CaMKII directly (by O‐Glycnacylation of serine 280) and by increasing reactive oxygen species and oxidizing methionines 281 and 282. The inactive CaMKII holoenzyme exists in a compact configuration. Intracellular Ca²⁺ increases lead to calcification of calmodulin (Ca²⁺/CaM) that binds to the C‐terminus of the regulatory domain. Ca²⁺/CaM binding induces CaMKII into an extended, active conformation that is inactivated after Ca²⁺/CaM unbinding. Post‐translational modifications to the regulatory domain keep CaMKII in a persistantly extended, active state even after Ca²⁺/CaM unbinding. ARB, angiotensin II receptor blockers; ACE, angiotensin converting enzyme; MR, mineralocorticoid receptor.