Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning

Abstract

This study aimed to investigate the role of the intrinsic cardiac nervous system in the mechanism of classical myocardial ischaemic preconditioning (IPC). Isolated perfused rat hearts were subjected to 35-min regional ischaemia and 60-min reperfusion. IPC was induced as three cycles of 5-min global ischaemia–reperfusion, and provided significant reduction in infarct size (IS/AAR = 14 ± 2% vs control IS/AAR = 48 ± 3%, p < 0.05). Treatment with the ganglionic antagonist, hexamethonium (50 μM), blocked IPC protection (IS/AAR = 37 ± 7%, p < 0.05 vs IPC). Moreover, the muscarinic antagonist, atropine (100 nM), also abrogated IPC-mediated protection (IS/AAR = 40 ± 3%, p < 0.05 vs IPC). This indicates that intrinsic cardiac ganglia remain intact in the Langendorff preparation and are important in the mechanism of IPC. In a second group of experiments, coronary effluent collected following IPC, from ex vivo perfused rat hearts, provided significant cardioprotection when perfused through a naïve isolated rat heart prior to induction of regional ischaemia–reperfusion injury (IRI) (IS/ARR = 19 ± 2, p < 0.05 vs control effluent). This protection was also abrogated by treating the naïve heart with hexamethonium, indicating the humoral trigger of IPC induces protection via an intrinsic neuronal mechanism (IS/AAR = 46 ± 5%, p < 0.05 vs IPC effluent). In addition, a large release in ACh was observed in coronary effluent was observed following IPC (IPCeff = 0.36 ± 0.03 μM vs C eff = 0.04 ± 0.04 μM, n = 4, p < 0.001). Interestingly, however, IPC effluent was not able to significantly protect isolated cardiomyocytes from simulated ischaemia–reperfusion injury (cell death = 45 ± 6%, p = 0.09 vs control effluent). In conclusion, IPC involves activation of the intrinsic cardiac nervous system, leading to release of ACh in the ventricles and induction of protection via activation of muscarinic receptors.

DUSP1 recuses diabetic nephropathy via repressing JNK‐Mff‐mitochondrial fission pathways

“…Consistently with our findings, previous studies have reported that DUSP1 downregulation was noted in fatty liver disease and cardiac ischemia reperfusion injury Pickard, Burke, Davidson, & Yellon, 2017;Zhou et al, 2018a) via modifying mitochondrial function, and that DUSP1 overexpression or pharmacological activation of DUSP1 retards or prevents the progression of nonalcoholic fatty liver F I G U R E 8 Downregulated DUSP1 induced by hyperglycemia amplified JNK pathway, promoting Mff phosphorylated activation. Increased Mff phosphorylation enhances fatal mitochondrial fission, leading to cellular oxidative stress, energy disorder, mitochondrial potential reduction, mPTP opening, cyt-c leakage into the cytoplasm, and the initiation of caspase-9-related glomerular mitochondrial apoptosis.…”

Inhibitory effect of melatonin on necroptosis via repressing the Ripk3‐PGAM5‐CypD‐mPTP pathway attenuates cardiac microvascular ischemia–reperfusion injury

“…Notably, recent observations indicate that CypD can undergo covalent modifications, 51 and phosphorylated CypD is associated with an increased susceptibility to mPTP opening. 52 In our study, HR treatment had no effect on VDAC, ANT, and CypD expression ( Figure 5D-G); however, the phosphorylation of Ser31 by CypD was significantly increased in response to HR injury but was statistically decreased to normal levels by melatonin through abrogating Ripk3 activation ( Figure 5E and H). Therefore, these findings suggest that Ripk3 augments mPTP opening via upregulating CypD phosphorylation.…”

“…Structurally, mPTP opening is facilitated by the binding of CypD to the inner mitochondrial membrane (IMM) . Notably, CypD binding to the IMM is enhanced by its phosphorylation .…”

MRI tracking reveals selective accumulation of stem cell-derived magneto-extracellular vesicles in sites of injury

“…We then applied our technology to study the distribution of i.v.-injected magneto-EVs in an IRinjured mouse heart, which was induced through the ligation of the left anterior descending (LAD) coronary artery for 35 min, followed by reperfusion (37) (Figs. 5A,B).…”