Melatonin prevents D rp1‐mediated mitochondrial fission in diabetic hearts through SIRT 1‐ PGC 1α pathway

Background Melatonin is a multifunctional indolamine and has a cardioprotective role in a variety of cardiovascular processes via antioxidant, anti‐inflammatory, antihypertensive, antithrombotic, and antilipemic effects. It has been reported that lower levels of circulating melatonin are significantly associated with a higher risk of acute myocardial infarction (AMI) and later cardiac remodeling. However, levels of melatonin in patients with dilated cardiomyopathy (DCM) and associations between melatonin levels and cardiac function remain unclear. Methods and Results We measured and compared plasma levels of melatonin in 61 control subjects, 81 AMI patients, and 77 DCM patients. Plasma levels of melatonin were progressively decreased from 71.9 pg/mL in the control group to 52.6 pg/mL in the DCM group and 21.9 pg/mL in the AMI group. Next, we examined associations of melatonin levels with parameters of laboratory data, echocardiography, and right‐heart catheterization. In the DCM patients, circulating melatonin showed significant correlations with both high‐sensitivity troponin T ( R = −0.422, P < 0.001) and cardiac output ( R = 0.431, P = 0.003), but not with B‐type natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), pulmonary artery wedge pressure, or pulmonary artery pressure. Conclusion Patients with not only AMI but also DCM had lower circulating melatonin levels. Circulating melatonin levels appear to correlate with myocardial injury and cardiac output in DCM patients.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Plasma levels of melatonin in dilated cardiomyopathy

Misaka

Yoshihisa

Yokokawa

et al. 2019

“…Moreover, melatonin was reported to increase in H 2 O 2 ‐exposed SH‐SY5Y cells the levels of autophagic factors beclin‐1 and LC3‐II, effects that were moderately reduced by EX527 . Some mitochondrial actions of melatonin were shown to be absent in Sirt1 –/– mice . In a rat COPD model, beneficial effects of melatonin, which included reduced NLRP3 inflammasome formation and IL‐1β levels, were inhibited by EX527 .…”

Section: Downstream Factors Of Melatonin's Actions With Relevance Tomentioning

confidence: 99%

Melatonin and inflammation—Story of a double‐edged blade

Hardeland

2018

329

350

Melatonin is an immune modulator that displays both pro‐ and anti‐inflammatory properties. Proinflammatory actions, which are well documented by many studies in isolated cells or leukocyte‐derived cell lines, can be assumed to enhance the resistance against pathogens. However, they can be detrimental in autoimmune diseases. Anti‐inflammatory actions are of particular medicinal interest, because they are observed in high‐grade inflammation such as sepsis, ischemia/reperfusion, and brain injury, and also in low‐grade inflammation during aging and in neurodegenerative diseases. The mechanisms contributing to anti‐inflammatory effects are manifold and comprise various pathways of secondary signaling. These include numerous antioxidant effects, downregulation of inducible and inhibition of neuronal NO synthases, downregulation of cyclooxygenase‐2, inhibition of high‐mobility group box‐1 signaling and toll‐like receptor‐4 activation, prevention of inflammasome NLRP3 activation, inhibition of NF‐κB activation and upregulation of nuclear factor erythroid 2‐related factor 2 (Nrf2). These effects are also reflected by downregulation of proinflammatory and upregulation of anti‐inflammatory cytokines. Proinflammatory actions of amyloid‐β peptides are reduced by enhancing α‐secretase and inhibition of β‐ and γ‐secretases. A particular role in melatonin's actions seems to be associated with the upregulation of sirtuin‐1 (SIRT1), which shares various effects known from melatonin and additionally interferes with the signaling by the mechanistic target of rapamycin (mTOR) and Notch, and reduces the expression of the proinflammatory lncRNA‐CCL2. The conclusion on a partial mediation by SIRT1 is supported by repeatedly observed inhibitions of melatonin effects by sirtuin inhibitors or knockdown.

“…Given its antioxidative, anti‐inflammatory, and antiapoptotic properties, melatonin is suggested to play a key role in attenuating reperfusion‐mediated myocardial damage . Moreover, the inhibitory effects of melatonin on mitochondrial fission have been extensively explored by our previous studies . Melatonin treatment inhibits mitochondrial fission in a manner dependent on AMPK pathway, sending a pro‐survival signal for reperfused hearts .…”

Section: Introductionmentioning

confidence: 99%

“…21,22 Moreover, the inhibitory effects of melatonin on mitochondrial fission have been extensively explored by our previous studies. 9,23,24 Melatonin treatment inhibits mitochondrial fission in a manner dependent on AMPK pathway, sending a pro-survival signal for reperfused hearts. 9 Besides, melatonin also modulates mitophagy activity via affecting FUN14 domain containing 1 (FUNDC1) expression.…”

Section: Introductionmentioning

confidence: 99%

Melatonin attenuates myocardial ischemia‐reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK‐OPA1 signaling pathways

Zhang

Wang

et al. 2019

272

202

Optic atrophy 1 (OPA1)‐related mitochondrial fusion and mitophagy are vital to sustain mitochondrial homeostasis under stress conditions. However, no study has confirmed whether OPA1‐related mitochondrial fusion/mitophagy is activated by melatonin and, consequently, attenuates cardiomyocyte death and mitochondrial stress in the setting of cardiac ischemia‐reperfusion (I/R) injury. Our results indicated that OPA1, mitochondrial fusion, and mitophagy were significantly repressed by I/R injury, accompanied by infarction area expansion, heart dysfunction, myocardial inflammation, and cardiomyocyte oxidative stress. However, melatonin treatment maintained myocardial function and cardiomyocyte viability, and these effects were highly dependent on OPA1‐related mitochondrial fusion/mitophagy. At the molecular level, OPA1‐related mitochondrial fusion/mitophagy, which was normalized by melatonin, substantially rectified the excessive mitochondrial fission, promoted mitochondria energy metabolism, sustained mitochondrial function, and blocked cardiomyocyte caspase‐9‐involved mitochondrial apoptosis. However, genetic approaches with a cardiac‐specific knockout of OPA1 abolished the beneficial effects of melatonin on cardiomyocyte survival and mitochondrial homeostasis in vivo and in vitro. Furthermore, we demonstrated that melatonin affected OPA1 stabilization via the AMPK signaling pathway and that blockade of AMPK repressed OPA1 expression and compromised the cardioprotective action of melatonin. Overall, our results confirm that OPA1‐related mitochondrial fusion/mitophagy is actually modulated by melatonin in the setting of cardiac I/R injury. Moreover, manipulation of the AMPK‐OPA1‐mitochondrial fusion/mitophagy axis via melatonin may be a novel therapeutic approach to reduce cardiac I/R injury.