Reply: Glucagon-like peptide-1 mediates cardioprotection by remote ischaemic conditioning

Basalay, Marina; Mastitskaya, Svetlana; Мрочек, А Г; Ackland, Gareth L.; Arroyo, Ana Gutierrez del; Sanchez, Jenifer; Sjöquist, Per-Ove; Pernow, John; Gourine, Alexander V.; Gourine, AV

doi:10.1093/cvr/cvw238

Cited by 6 publications

(6 citation statements)

References 13 publications

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“…We previously demonstrated that RIC is critically dependent on autonomic parasympathetic mechanisms [62] and it is plausible that its clinical efficacy is compromised by the inability of many patients to recruit vagal activity. As we reasoned in our earlier publications [7,25,26,63] and reported supporting evidence [1,56], vagal tone decreases with age and could be severely diminished or even absent in many disease states, rendering many patients unable to recruit innate mechanisms of inter-organ protection. If GLP-1 is a common mediator of cardio-and neuroprotection induced by RIC, then administration of GLP-1 stable analogues may offer a better therapeutic solution for the treatment of acute myocardial infarction and ischaemic stroke, especially in patients with autonomic dysfunction.…”

Section: Discussionmentioning

confidence: 63%

Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke

et al. 2021

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Stroke remains one of the most common causes of death and disability worldwide. Several preclinical studies demonstrated that the brain can be effectively protected against ischaemic stroke by two seemingly distinct treatments: remote ischaemic conditioning (RIC), involving cycles of ischaemia/reperfusion applied to a peripheral organ or tissue, or by systemic administration of glucagon-like-peptide-1 (GLP-1) receptor (GLP-1R) agonists. The mechanisms underlying RIC- and GLP-1-induced neuroprotection are not completely understood. In this study, we tested the hypothesis that GLP-1 mediates neuroprotection induced by RIC and investigated the effect of GLP-1R activation on cerebral blood vessels, as a potential mechanism of GLP-1-induced protection against ischaemic stroke. A rat model of ischaemic stroke (90 min of middle cerebral artery occlusion followed by 24-h reperfusion) was used. RIC was induced by 4 cycles of 5 min left hind limb ischaemia interleaved with 5-min reperfusion periods. RIC markedly (by ~ 80%) reduced the cerebral infarct size and improved the neurological score. The neuroprotection established by RIC was abolished by systemic blockade of GLP-1R with a specific antagonist Exendin(9–39). In the cerebral cortex of GLP-1R reporter mice, ~ 70% of cortical arterioles displayed GLP-1R expression. In acute brain slices of the rat cerebral cortex, activation of GLP-1R with an agonist Exendin-4 had a strong dilatory effect on cortical arterioles and effectively reversed arteriolar constrictions induced by metabolite lactate or oxygen and glucose deprivation, as an ex vivo model of ischaemic stroke. In anaesthetised rats, Exendin-4 induced lasting increases in brain tissue PO2, indicative of increased cerebral blood flow. These results demonstrate that neuroprotection against ischaemic stroke established by remote ischaemic conditioning is mediated by a mechanism involving GLP-1R signalling. Potent dilatory effect of GLP-1R activation on cortical arterioles suggests that the neuroprotection in this model is mediated via modulation of cerebral blood flow and improved brain perfusion.

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Section: Discussionmentioning

confidence: 63%

Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke

et al. 2021

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“…RIPC increased plasma GLP-1 level [150] however, whether this increase in plasma GLP-1 is physiological relevant warrants further discussion. GLP-1 has a low half-life (couple of minutes) and majority of the intestine-produced GLP-1 is rapidly degraded [151, 152]. However, GLP-1 has a longer lasting beneficial effect even when the circulating level drops to normal level [151].…”

Section: Circulating Mediators Of Ischemic Conditioningmentioning

confidence: 99%

“…GLP-1 has a low half-life (couple of minutes) and majority of the intestine-produced GLP-1 is rapidly degraded [151, 152]. However, GLP-1 has a longer lasting beneficial effect even when the circulating level drops to normal level [151]. Previously, Pyke and colleagues suggested that ventricular cardiomyocytes do not express GLP-1R [153].…”

Section: Circulating Mediators Of Ischemic Conditioningmentioning

confidence: 99%

Circulating mediators of remote ischemic preconditioning: search for the missing link between non-lethal ischemia and cardioprotection

et al. 2019

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Acute myocardial infarction (AMI) is one of the leading causes of mortality and morbidity worldwide. There has been an extensive search for cardioprotective therapies to reduce myocardial ischemia-reperfusion (I/R) injury. Remote ischemic preconditioning (RIPC) is a phenomenon that relies on the body's endogenous protective modalities against I/R injury. In RIPC, non-lethal brief I/R of one organ or tissue confers protection against subsequent lethal I/R injury in an organ remote to the briefly ischemic organ or tissue. Initially it was believed to be limited to direct myocardial protection, however it soon became apparent that RIPC applied to other organs such as kidney, liver, intestine, skeletal muscle can reduce myocardial infarct size. Intriguing discoveries have been made in extending the concept of RIPC to other organs than the heart. Over the years, the underlying mechanisms of RIPC have been widely sought and discussed. The involvement of blood-borne factors as mediators of RIPC has been suggested by a number of research groups. The main purpose of this review article is to summarize the possible circulating mediators of RIPC, and recent studies to establish the clinical efficacy of these mediators in cardioprotection from lethal I/R injury.

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“…Since the first demonstration of the possibility to transfer ischaemic preconditioning cardioprotection with blood [ 32 ], the attention of several research groups has focused on identifying the humoral factor responsible for RIPre. Several candidate humoral factors of RIC have been proposed, including stromal cell-derived factor-1 [ 30 ], nitrite/nitric oxide [ 110 ], interleukin-1α [ 41 ], interleukin-10 [ 19 ], microRNA-144 [ 88 ], apolipoprotein A-I [ 57 ], alpha-ketoglutarate-dependent dioxygenase Egln1 [ 101 ] and glucagon-like peptide-1 (GLP-1) [ 7 , 8 ]. However, for the purpose of this review, we focus on two of the proposed humoral mediators that are most relevant to the ‘neural hypothesis’ of RIC, namely nitrite/nitric oxide [ 110 ] and GLP-1 [ 7 , 8 ].…”

Section: The Mechanisms Of Cardioprotection By Remote Ischaemic Condimentioning

confidence: 99%

“…The efficacy of GLP-1R agonists in limiting infarct size has also been shown in clinical trials on STEMI patients [ 90 , 144 ]. Later, Basalay et al showed that GLP-1 mediates cardioprotection by RIC, and demonstrated that cardioprotection induced by GLP-1R activation is mediated by a mechanism involving M3 muscarinic receptors [ 7 , 8 ]. The location of these M3 muscarinic receptors, mediating the infarct-limiting effect of RIPre, is not yet established.…”

Section: The Mechanisms Of Cardioprotection By Remote Ischaemic Condimentioning

confidence: 99%

Neural mechanisms in remote ischaemic conditioning in the heart and brain: mechanistic and translational aspects

et al. 2018

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Remote ischaemic conditioning (RIC) is a promising method of cardioprotection, with numerous clinical studies having demonstrated its ability to reduce myocardial infarct size and improve prognosis. On the other hand, there are several clinical trials, in particular those conducted in the setting of elective cardiac surgery, that have failed to show any benefit of RIC. These contradictory data indicate that there is insufficient understanding of the mechanisms underlying RIC. RIC is now known to signal indiscriminately, protecting not only the heart, but also other organs. In particular, experimental studies have demonstrated that it is able to reduce infarct size in an acute ischaemic stroke model. However, the mechanisms underlying RIC-induced neuroprotection are even less well understood than for cardioprotection. The existence of bidirectional feedback interactions between the heart and the brain suggests that the mechanisms of RIC-induced neuroprotection and cardioprotection should be studied as a whole. This review, therefore, addresses the topic of the neural component of the RIC mechanism.

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Reply: Glucagon-like peptide-1 mediates cardioprotection by remote ischaemic conditioning

Cited by 6 publications

References 13 publications

Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke

Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke

Circulating mediators of remote ischemic preconditioning: search for the missing link between non-lethal ischemia and cardioprotection

Neural mechanisms in remote ischaemic conditioning in the heart and brain: mechanistic and translational aspects

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