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

View Article: PubMed Central - PubMed

ABSTRACT

In addition to their anti-bacterial action, tetracyclines also have complex biological effects, including the modification of mitochondrial protein synthesis, metabolism and gene-expression. Long-term clinical studies have been performed using tetracyclines, without significant side effects. Previous studies demonstrated that doxycycline (DOX), a major tetracyclin antibiotic, exerted a protective effect in animal models of heart failure; however, its exact molecular mechanism is still unknown. Here, we provide the first evidence that DOX reduces oxidative stress—induced mitochondrial fragmentation and depolarization in H9c2 cardiomyocytes and beneficially alters the expression of Mfn-2, OPA-1 and Drp-1 –the main regulators of mitochondrial fusion and fission—in our isoproterenol (ISO)–induced heart failure model, ultimately decreasing the severity of heart failure. In mitochondria, oxidative stress causes a shift toward fission which leads to mitochondrial fragmentation and cell death. Protecting mitochondria from oxidative stress, and the regulation of mitochondrial dynamics by drugs that shift the balance toward fusion, could be a novel therapeutic approach for heart failure. On the basis of our findings, we raise the possibility that DOX could be a novel therapeutic agent in the future treatment of heart failure.

No MeSH data available.


Related in: MedlinePlus

DOX favorably modulates the expression of Mfn-2, OPA-1 and the phophoryltaion of Drp-1.Representative western blot analysis of Mfn-2, OPA-1, Drp-1 and pDrp-1Ser616 and densitometric evaluation is shown. PhosphoDrp-1Ser616 bands were normalized to the appropriate Drp-1 bands. Representative blots and bar diagrams of three independent experiments are presented. C: control animals, ISO: animals 8 weeks after ISO administration; ISO + DOX: animals treated with doxycycline, 8 weeks after ISO administration; DOX: animals treated with doxycycline for 8 weeks. Values are mean ± SEM. # P < 0.05 vs control, *P < 0.05 vs. ISO.
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pone.0175195.g005: DOX favorably modulates the expression of Mfn-2, OPA-1 and the phophoryltaion of Drp-1.Representative western blot analysis of Mfn-2, OPA-1, Drp-1 and pDrp-1Ser616 and densitometric evaluation is shown. PhosphoDrp-1Ser616 bands were normalized to the appropriate Drp-1 bands. Representative blots and bar diagrams of three independent experiments are presented. C: control animals, ISO: animals 8 weeks after ISO administration; ISO + DOX: animals treated with doxycycline, 8 weeks after ISO administration; DOX: animals treated with doxycycline for 8 weeks. Values are mean ± SEM. # P < 0.05 vs control, *P < 0.05 vs. ISO.

Mentions: OPA-1 expression significantly increased in the DOX treated groups compared to the control and ISO groups (P < 0.05, control vs. DOX and P < 0.05, ISO vs. ISO+DOX) whereas the expression of Mfn-2 decreased significantly in the ISO+DOX group compared to the ISO group (P < 0.05, ISO vs. ISO+DOX). The phosphorylation level of Drp-1Ser616 increased significantly in the ISO group and decreased significantly in the ISO+DOX group (P < 0.05, C vs. ISO and P < 0.05, ISO vs. ISO+DOX). Protein levels were measured with Nanodrop and GAPDH was used as loading control (Fig 5).


Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure
DOX favorably modulates the expression of Mfn-2, OPA-1 and the phophoryltaion of Drp-1.Representative western blot analysis of Mfn-2, OPA-1, Drp-1 and pDrp-1Ser616 and densitometric evaluation is shown. PhosphoDrp-1Ser616 bands were normalized to the appropriate Drp-1 bands. Representative blots and bar diagrams of three independent experiments are presented. C: control animals, ISO: animals 8 weeks after ISO administration; ISO + DOX: animals treated with doxycycline, 8 weeks after ISO administration; DOX: animals treated with doxycycline for 8 weeks. Values are mean ± SEM. # P < 0.05 vs control, *P < 0.05 vs. ISO.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5383248&req=5

pone.0175195.g005: DOX favorably modulates the expression of Mfn-2, OPA-1 and the phophoryltaion of Drp-1.Representative western blot analysis of Mfn-2, OPA-1, Drp-1 and pDrp-1Ser616 and densitometric evaluation is shown. PhosphoDrp-1Ser616 bands were normalized to the appropriate Drp-1 bands. Representative blots and bar diagrams of three independent experiments are presented. C: control animals, ISO: animals 8 weeks after ISO administration; ISO + DOX: animals treated with doxycycline, 8 weeks after ISO administration; DOX: animals treated with doxycycline for 8 weeks. Values are mean ± SEM. # P < 0.05 vs control, *P < 0.05 vs. ISO.
Mentions: OPA-1 expression significantly increased in the DOX treated groups compared to the control and ISO groups (P < 0.05, control vs. DOX and P < 0.05, ISO vs. ISO+DOX) whereas the expression of Mfn-2 decreased significantly in the ISO+DOX group compared to the ISO group (P < 0.05, ISO vs. ISO+DOX). The phosphorylation level of Drp-1Ser616 increased significantly in the ISO group and decreased significantly in the ISO+DOX group (P < 0.05, C vs. ISO and P < 0.05, ISO vs. ISO+DOX). Protein levels were measured with Nanodrop and GAPDH was used as loading control (Fig 5).

View Article: PubMed Central - PubMed

ABSTRACT

In addition to their anti-bacterial action, tetracyclines also have complex biological effects, including the modification of mitochondrial protein synthesis, metabolism and gene-expression. Long-term clinical studies have been performed using tetracyclines, without significant side effects. Previous studies demonstrated that doxycycline (DOX), a major tetracyclin antibiotic, exerted a protective effect in animal models of heart failure; however, its exact molecular mechanism is still unknown. Here, we provide the first evidence that DOX reduces oxidative stress&mdash;induced mitochondrial fragmentation and depolarization in H9c2 cardiomyocytes and beneficially alters the expression of Mfn-2, OPA-1 and Drp-1 &ndash;the main regulators of mitochondrial fusion and fission&mdash;in our isoproterenol (ISO)&ndash;induced heart failure model, ultimately decreasing the severity of heart failure. In mitochondria, oxidative stress causes a shift toward fission which leads to mitochondrial fragmentation and cell death. Protecting mitochondria from oxidative stress, and the regulation of mitochondrial dynamics by drugs that shift the balance toward fusion, could be a novel therapeutic approach for heart failure. On the basis of our findings, we raise the possibility that DOX could be a novel therapeutic agent in the future treatment of heart failure.

No MeSH data available.


Related in: MedlinePlus