Humanin prevents brain mitochondrial dysfunction in a cardiac ischaemia–reperfusion injury model

Abstract

New Findings r What is the central question of this study?Myocardial ischaemia-reperfusion (I/R) injury causes interference in the systemic circulation and damages not only the heart but also several vital organs, including the brain. Recently, a novel peptide called humanin has been shown to exert potent neuroprotective effects. However, the effect of humanin on the brain during cardiac I/R injury has not yet been investigated. r What is the main finding and its importance?The I/R injury caused blood-brain barrier breakdown, increased brain oxidative stress and resulted in mitochondrial dysfunction. Only the humanin treatment before ischaemia attenuated brain mitochondrial dysfunction, but it did not prevent blood-brain barrier breakdown or brain oxidative stress. Humanin treatment during ischaemia and in the reperfusion period provided no neuroprotection. These findings indicate that humanin exerted neuroprotection during cardiac I/R injury via improved brain mitochondrial function.Myocardial ischaemia-reperfusion (I/R) injury causes interference in the systemic circulation and damages not only the heart but also several vital organs, including the brain. Nevertheless, limited information is available regarding the effect of cardiac I/R injury on the brain, including blood-brain barrier (BBB) breakdown, brain oxidative stress and mitochondrial function. Recently, a novel peptide called humanin has been shown to exert potent neuroprotective effects. However, the effect of humanin on the brain during cardiac I/R injury has not yet been investigated. Forty-two male Wistar rats were divided into the following two groups: an I/R group, which was subjected to a 30 min left anterior descending coronary artery occlusion followed by 120 min reperfusion (I/R group; n = 36); and a sham group (n = 6). The I/R group was divided into six subgroups. Each subgroup was given either vehicle or humanin analogue (84 μg kg −1 , i.v.) at three different time points, namely before ischaemia, during ischaemia or at the onset of reperfusion. At the end of the experimental protocol, animals were killed and the brains removed for determination of mitochondrial function, oxidative stress and Western blot analyses. The I/R injury caused BBB breakdown, increased brain oxidative stress and resulted in mitochondrial dysfunction. Only the humanin treatment before ischaemia attenuated brain mitochondrial dysfunction, but it did not prevent BBB breakdown or brain

Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway

“…It has been documented that humanin may alter mitochondrial oxidative phosphorylation and ATP production; however, the exact molecular mechanisms are not well understood (8). A study by Kumfu et al (35) reported that humanin may prevent brain mitochondrial dysfunction in a model of cardiac ischemia-reperfusion injury. The results of the present study demonstrated that HNG inhibited mitochondrial dysfunction-mediated apoptosis via Jak2/Stat3.…”

The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets

“…These effects were attenuated by HNG treatment, which protects mitochondria through decreased complex I activity [101]. Similarly, HNG protects brain mitochondria during AMI and MRI, reducing tau hyperphosphorylation, Aβ accumulation and apoptosis [102,103]. However, in the porcine model system, the cardioprotective effect of HNG treatment was observed only for short-term ischemia, with no significant protective effect with prolonged ischemia [104].…”

“…protects brain mitochondria during AMI and MRI, reducing tau hyperphosphorylation, Aβ accumulation and apoptosis [102,103] inhibits platelet aggregation, P-selectin expression, αIIbβ3 activation and adhesion under flow conditions; enhances tubulin acetylation and inhibits microtubule depolymerization [105]…”

RETRACTED ARTICLE: Astragalin alleviates cerebral ischemia-reperfusion injury by improving anti-oxidant and anti-inflammatory activities and inhibiting apoptosis pathway in rats

“…Brain I/R injury is a complex pathophysiological process. Brain blood flow interruption and reperfusion damage the brain cells is a rapid cascade reaction [12,13]. This cascade reaction includes many links, such as energy metabolism, cytotoxicity, increased release of excitatory amino acids, intracellular calcium homeostasis, free radical production, and activation of apoptotic genes [14].…”