Acetylcholine from vagal stimulation protects cardiomyocytes against ischemia and hypoxia involving additive non‐hypoxic induction of HIF‐1α

Abstract

Electrical stimulation of the vagal efferent nerve improves the survival of myocardial infarcted rats. However, the mechanism for this beneficial effect is unclear. We investigated the effect of acetylcholine (ACh) on hypoxia-inducible factor (HIF)-1a using rat cardiomyocytes under normoxia and hypoxia. ACh posttranslationally regulated HIF-1a and increased its protein level under normoxia. ACh increased Akt phosphorylation, and wortmannin or atropine blocked this effect. Hypoxia-induced caspase-3 activation and mitochondrial membrane potential collapse were prevented by ACh. Dominant-negative HIF-1a inhibited the cell protective effect of ACh. In acute myocardial ischemia, vagal nerve stimulation increased HIF-1a expression and reduced the infarct size. These results suggest that ACh and vagal stimulation protect cardiomyocytes through the PI3K/Akt/HIF-1a pathway.

Donepezil, an acetylcholinesterase inhibitor against Alzheimer's dementia, promotes angiogenesis in an ischemic hindlimb model

“…Specifically, donepezil activated protein expression of VEGF and ChAT, a critical enzyme for de novo ACh synthesis, accelerated endothelial cell proliferation, and inhibited apoptosis, partly independent of cholinergic receptors. These results suggest that donepezil regulates angiogenesis through a non-hypoxic HIF-1 induction pathway, which might be triggered by increased ACh [3,4]. Donepezil was developed to treat patients with Alzheimer's disease as an acetylcholinesterase inhibitor [12,13].…”

“…Our previous study demonstrated that ACh triggers a cell survival signal pathway and transactivates HIF-1 -regulated downstream genes, preventing cells from hypoxia-induced apoptosis [3]. This prompted us to speculate that cholinergic stimuli also possess angiogenesis-promoting effects.…”

“…Our recent study demonstrated that ACh directly transduces cell survival signal through the muscarinic receptor, activates the PI3K/Akt/HIF-1 /VEGF pathway, inhibits collapse of mitochondrial membrane potential, and inactivates caspase-3 in cardiomyocytes subjected to hypoxia [3]. Because both survival and angiogenic pathways share common signaling molecules through HIF-1 /VEGF, these results prompted us to speculate the involvement of ACh in modulation of angiogenesis.…”

Cardioprotective effects of fucoidan against hypoxia-induced apoptosis in H9c2 cardiomyoblast cells

“…Thus, therapeutic strategies focusing on inhibiting myocardial cell apoptosis may be beneficial to impede the occurrence and progression of these cardiovascular diseases. It has been proposed that cardiac myocyte cell loss is the result of apoptosis and is of great importance to various cardiovascular diseases (Gao et al, 2013), and hypoxia is regarded as a key initiator to arouse the loss of cardiac myocyte cells (Kakinuma et al, 2005). Therefore, suppression of hypoxia-induced apoptosis might be beneficial to block the occurrence and progression of many heart diseases.…”

Donepezil, Therapeutic Acetylcholinesterase Inhibitor, Prevents the Progression of Ventricular Dysfunction by Promoting Myocardial Glucose Utilization in Rat Model of Chronic Heart Failure Following Myocardial Infarction

“…The pharmacological action of donepezil is based on an increase in the acetylcholine (ACh) level via inhibition of acetylcholinesterase activity. ACh has been reported to upregulate hypoxia-inducible factor (HIF)-1 alpha even in normoxic conditions [44]. HIF-1 alpha is well known as a master transcriptional factor that positively regulates the expression of glucose metabolism-related genes including GLUTs [45].…”