Abstract
Autophagy, macroautophagy and chaperone-mediated autophagy (CMA), are upregulated in pressure overload (PO) hypertrophy. In this study, we targeted this process at its induction using 3 methyladenine and at the lysosomal level using chloroquine and evaluated the effects of these modulations on cardiac function and myocyte ultrastructure. Sprague–Dawley rats weighing 200 g were subjected to ascending aortic banding. After 1 week of PO, animals were randomized to receive 3 methyladenine versus chloroquine, intraperitoneally, for 2 weeks at a dose of 40 and 50 mg/kg/day, respectively. Saline injection was used as control. Chloroquine treatment, in PO, resulted in regression in cardiac hypertrophy but with significant impairments in cardiac relaxation and contractility. Ultrastructurally, chloroquine accentuated mitochondrial fragmentation and cristae destruction with a plethora of autophagosomes containing collapsed mitochondria and lysosomal lamellar bodies. In contrast, 3 methyladenine improved cardiac function and attenuated mitochondrial fragmentation and autophagososme formation. Markers of macroautophagy and CMA were significantly decreased in the chloroquine group; whereas 3 methyladenine treatment significantly attenuated macroautophagy with a compensatory increase in CMA. Furthermore, chloroquine accentuated PO induced oxidative stress through the further decrease in the expression of manganese superoxide dismutase; whereas, 3 MA had a completely opposite effect. Taken together, these data suggest that high-dose chloroquine, in addition to its effect on the autophagy-lysosome pathway, significantly impairs mitochondrial antioxidant buffering capacity and accentuates oxidative stress and mitochondrial dysfunction in PO hypertrophy; highlighting, the cautious administration of this drug in high oxidative stress conditions, such as pathological hypertrophy or heart failure.
Highlights
Autophagy is a cellular process involved in the recycling of damaged proteins and organelles in the cell (Klionsky and Codogno 2013; Jin and Klionsky 2014)
Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society
We showed for the first time that 3-methyladenine, in addition to its inhibitory effect on the canonical activation of autophagy via the inhibition of phosphatidylinositol 3-kinase (PI3K) class 3, attenuates JNK signaling leading to the decreased transcription of BNIP3 gene in Pressure Overload Hypertrophy (POH) and inhibits mitophagy as well as apoptosis (Chaanine et al 2012, 2013)
Summary
Autophagy is a cellular process involved in the recycling of damaged proteins and organelles in the cell (Klionsky and Codogno 2013; Jin and Klionsky 2014). We showed for the first time that 3-methyladenine, in addition to its inhibitory effect on the canonical activation of autophagy via the inhibition of phosphatidylinositol 3-kinase (PI3K) class 3, attenuates JNK signaling leading to the decreased transcription of BNIP3 gene in POH and inhibits mitophagy as well as apoptosis (Chaanine et al 2012, 2013). Since both types of autophagy, macroautophagy and chaperone-mediated autophagy, are activated in POH, the aim of this study was to understand the effect of modulating this process at two different sites. We used high doses of chloroquine in this study to modulate the autophagic activity similar to what is currently being used in cancer therapy (up to 1200 mg per day of chloroquine) and not in the treatment of malaria or other rheumatologic diseases where a much lower dose of chloroquine is usually used
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