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

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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.


Representative echocardiographic M-mode images of left ventricles of control, DOX, ISO and ISO+DOX groups.
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pone.0175195.g003: Representative echocardiographic M-mode images of left ventricles of control, DOX, ISO and ISO+DOX groups.

Mentions: The echocardiographic parameters of animals did not differ significantly from each other at the beginning of the study. Heart rate did not differ significantly among the groups during the anesthesia. The thickness of the septum and posterior wall were also increased in the ISO group (indicating the presence of ventricular hypertrophy) compared to the control group (P < 0.05, ISO vs. C). Doxycycline treatment significantly reduced these unfavorable alterations. Systolic left ventricular function (EF %) and fractional shortening (FS %) were significantly lower in the ISO group (P < 0.05, ISO vs. C) and these deterioration was significantly improved by doxycycline administration (P < 0.05, ISO vs. ISO+DOX; Table 1; Fig 3).


Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure
Representative echocardiographic M-mode images of left ventricles of control, DOX, ISO and ISO+DOX groups.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0175195.g003: Representative echocardiographic M-mode images of left ventricles of control, DOX, ISO and ISO+DOX groups.
Mentions: The echocardiographic parameters of animals did not differ significantly from each other at the beginning of the study. Heart rate did not differ significantly among the groups during the anesthesia. The thickness of the septum and posterior wall were also increased in the ISO group (indicating the presence of ventricular hypertrophy) compared to the control group (P < 0.05, ISO vs. C). Doxycycline treatment significantly reduced these unfavorable alterations. Systolic left ventricular function (EF %) and fractional shortening (FS %) were significantly lower in the ISO group (P < 0.05, ISO vs. C) and these deterioration was significantly improved by doxycycline administration (P < 0.05, ISO vs. ISO+DOX; Table 1; Fig 3).

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.