Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure

Riba, Adam; Deres, László; Erős, Krisztián; Szabó, Andrea; Magyar, Klara; Sümegi, Balázs; Tóth, Kálmán; Halmosi, Róbert; Szabados, Eszter

doi:10.1371/journal.pone.0175195

Cited by 42 publications

(36 citation statements)

References 49 publications

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“…Atria and great vessels were trimmed from the ventricles; the weight of the ventricles was measured and normalized to body mass. Afterward, ventricles were fixed in 10% formalin for histology or freeze clamped for Western blot analysis [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

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Cardioprotective Effect of Resveratrol in a Postinfarction Heart Failure Model

Riba

Deres

Sümegi

et al. 2017

Oxidative Medicine and Cellular Longevity

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100

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Despite great advances in therapies observed during the last decades, heart failure (HF) remained a major health problem in western countries. In order to further improve symptoms and survival in patients with heart failure, novel therapeutic strategies are needed. In some animal models of HF resveratrol (RES), it was able to prevent cardiac hypertrophy, contractile dysfunction, and remodeling. Several molecular mechanisms are thought to be involved in its protective effects, such as inhibition of prohypertrophic signaling molecules, improvement of myocardial Ca2+ handling, regulation of autophagy, and the reduction of oxidative stress and inflammation. In our present study, we wished to further examine the effects of RES on prosurvival (Akt-1, GSK-3β) and stress signaling (p38-MAPK, ERK 1/2, and MKP-1) pathways, on oxidative stress (iNOS, COX-2 activity, and ROS formation), and ultimately on left ventricular function, hypertrophy and fibrosis in a murine, and isoproterenol- (ISO-) induced postinfarction heart failure model. RES treatment improved left ventricle function, decreased interstitial fibrosis, cardiac hypertrophy, and the level of plasma BNP induced by ISO treatment. ISO also increased the activation of P38-MAPK, ERK1/2Thr183-Tyr185, COX-2, iNOS, and ROS formation and decreased the phosphorylation of Akt-1, GSK-3β, and MKP-1, which were favorably influenced by RES. According to our results, regulation of these pathways may also contribute to the beneficial effects of RES in HF.

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Section: Methodsmentioning

confidence: 99%

“…Left ventricular (LV), ejection fraction (EF), LV end-diastolic volume, LV end-systolic volume, and the thickness of the septum and posterior wall were determined. EF (percentage) was calculated by 100 × [(LVEDV−LVESV)/LVEDV] [ 16 , 17 ].…”

Section: Methodsmentioning

confidence: 99%

Cardioprotective Effect of Resveratrol in a Postinfarction Heart Failure Model

Riba

Deres

Sümegi

et al. 2017

Oxidative Medicine and Cellular Longevity

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100

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“…In other cells types, necroptosis activation can enhance aerobic respiration and ROS production (Yang et al, 2018). As ROS can trigger mitochondrial fragmentation by diverse mechanisms, including Drp-1 activation (Abuarab et al, 2017;Riba et al, 2017), necroptosis-dependent mitochondrial fragmentation could represent an executioner mechanism for axonal degeneration after injury.…”

Section: Necroptosis Links Mitochondrial Fragmentation To Axonal Degementioning

confidence: 99%

Axonal Degeneration Is Mediated by Necroptosis Activation

et al. 2019

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Axonal degeneration, which contributes to functional impairment in several disorders of the nervous system, is an important target for neuroprotection. Several individual factors and subcellular events have been implicated in axonal degeneration, but researchers have so far been unable to identify an integrative signaling pathway activating this self-destructive process. Through pharmacological and genetic approaches, we tested whether necroptosis, a regulated cell-death mechanism implicated in the pathogenesis of several neurodegenerative diseases, is involved in axonal degeneration. Pharmacological inhibition of the necroptotic kinase RIPK1 using necrostatin-1 strongly delayed axonal degeneration in the peripheral nervous system and CNS of wild-type mice of either sex and protected in vitro sensory axons from degeneration after mechanical and toxic insults. These effects were also observed after genetic knock-down of RIPK3, a second key regulator of necroptosis, and the downstream effector MLKL (Mixed Lineage Kinase Domain-Like). RIPK1 inhibition prevented mitochondrial fragmentation in vitro and in vivo, a typical feature of necrotic death, and inhibition of mitochondrial fission by Mdivi also resulted in reduced axonal loss in damaged nerves. Furthermore, electrophysiological analysis demonstrated that inhibition of necroptosis delays not only the morphological degeneration of axons, but also the loss of their electrophysiological function after nerve injury. Activation of the necroptotic pathway early during injury-induced axonal degeneration was made evident by increased phosphorylation of the downstream effector MLKL. Our results demonstrate that axonal degeneration proceeds by necroptosis, thus defining a novel mechanistic framework in the axonal degenerative cascade for therapeutic interventions in a wide variety of conditions that lead to neuronal loss and functional impairment.

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“…It has yet to be demonstrated whether or not these new agents will be safe and can help to overcome the poor survival and high rates of early death in this highrisk group of patients. Also doxycycline, which may have a cardioprotective effect and may lead to reduced fibril formation, should be studied for its clinical potential in this high-risk population [37][38][39]. Finally, early diagnosis of the disease remains crucial, since early treatment is associated with better survival outcomes.…”

Section: Characteristicmentioning

confidence: 99%