Identifying the Source of a Humoral Factor of Remote (Pre)Conditioning Cardioprotection

Abstract

Signalling pathways underlying the phenomenon of remote ischaemic preconditioning (RPc) cardioprotection are not completely understood. The existing evidence agrees that intact sensory innervation of the remote tissue/organ is required for the release into the systemic circulation of preconditioning factor(s) capable of protecting a transplanted or isolated heart. However, the source and molecular identities of these factors remain unknown. Since the efficacy of RPc cardioprotection is critically dependent upon vagal activity and muscarinic mechanisms, we hypothesized that the humoral RPc factor is produced by the internal organ(s), which receive rich parasympathetic innervation. In a rat model of myocardial ischaemia/reperfusion injury we determined the efficacy of limb RPc in establishing cardioprotection after denervation of various visceral organs by sectioning celiac, hepatic, anterior and posterior gastric branches of the vagus nerve. Electrical stimulation was applied to individually sectioned branches to determine whether enhanced vagal input to a particular target area is sufficient to establish cardioprotection. It was found that RPc cardioprotection is abolished in conditions of either total subdiaphragmatic vagotomy, gastric vagotomy or sectioning of the posterior gastric branch. The efficacy of RPc cardioprotection was preserved when hepatic, celiac or anterior gastric vagal branches were cut. In the absence of remote ischaemia/reperfusion, electrical stimulation of the posterior gastric branch reduced infarct size, mimicking the effect of RPc. These data suggest that the circulating factor (or factors) of RPc are produced and released into the systemic circulation by the visceral organ(s) innervated by the posterior gastric branch of the vagus nerve.

Glucagon-like peptide-1 (GLP-1) mediates cardioprotection by remote ischaemic conditioning

“…An established rat model of myocardial ischaemia/reperfusion injury was used 3 , 13 , 21 . The heart was exposed via a left thoracotomy and a 5–0 monofilament polypropylene suture was passed around the left anterior descending coronary (LAD) artery to induce a temporary occlusion.…”

“…The area at risk and the necrotic area were determined by computerized planimetry, normalized to the weight of each slice, with the degree of necrosis (i.e. infarct size) expressed as the percentage of area at risk, as described 3 , 13 , 21 …”

“…There is evidence that RIPre cardioprotection is abolished in conditions of either cervical 3 or subdiaphragmatic 21 vagotomy. However, the role of parasympathetic mechanisms in mediating RIPer cardioprotection remains unknown.…”

“…RIPre was reported to be abolished by selective genetic inhibition of brainstem vagal preganglionic neurones, 13 muscarinic receptor blockade, 13 , 14 bilateral cervical vagotomy 3 or sectioning of the posterior gastric branch of the vagus nerve 21 . Electrical stimulation of the whole vagus nerve at the cervical level 22 , 23 or isolated posterior gastric branch of the vagus 21 establishes cardioprotection. These data suggest that visceral organs, innervated by the posterior gastric branch of the vagus nerve, are the likely source of a humoral factor (or factors) of RIc cardioprotection.…”

Review of remote ischemic preconditioning: from laboratory studies to clinical trials

“…Cardioprotection by RIPC seems to be dependent on afferent innervation of the remote organ and intact parasympathetic activity, while delayed remote postconditioning relies on different signaling pathways (14). The recent study in rat model have shown that the circulating factors of RIPC are produced and released into the systemic circulation by the visceral organs innervated by the posterior gastric branch of the vagus nerve (15). In brain protection, neuronal involvement in RIPC has been reported in several studies, mainly via a blockade of sensory inputs that reduced the beneficial effects of RIPC (16,17).…”