Mitochondrial aldehyde dehydrogenase protects against doxorubicin cardiotoxicity through a transient receptor potential channel vanilloid 1-mediated mechanism

Article

Author: Ming Yuan ; Jun Ren ; Xiaoming Wang ; Wei Ge ; Asli F. Ceylan

Cardiotoxicity is one of the major life-threatening effects encountered in cancer chemotherapy with doxorubicin and other anthracyclines. Mitochondrial aldehyde dehydrogenase (ALDH2) may alleviate doxorubicin toxicity although the mechanism remains elusive. This study was designed to evaluate the impact of ALDH2 overexpression on doxorubicin-induced myocardial damage with a focus on mitochondrial injury. Wild-type (WT) and transgenic mice overexpressing ALDH2 driven by chicken β-actin promoter were challenged with doxorubicin (15mg/kg, single i.p. injection, for 6days) and cardiac mechanical function was assessed using the echocardiographic and IonOptix systems. Western blot analysis was used to evaluate intracellular Ca(2+) regulatory and mitochondrial proteins, PKA and its downstream signal eNOS. Doxorubicin challenge altered cardiac geometry and function evidenced by enlarged left ventricular end systolic and diastolic diameters, decreased factional shortening, cell shortening and intracellular Ca(2+) rise, prolonged relengthening and intracellular Ca(2+) decay, the effects of which were attenuated by ALDH2. Doxorubicin challenge compromised mitochondrial integrity and upregulated 4-HNE and UCP-2 levels while downregulating levels of TRPV1, SERCA2a and PGC-1α, the effects of which were alleviated by ALDH2. Doxorubicin-induced cardiac functional defect and apoptosis were reversed by the TRPV1 agonist SA13353 and the ALDH-2 agonist Alda-1 whereas the TRPV1 antagonist capsazepine nullified ALDH2/Alda-1-induced protection. Doxorubicin suppressed phosphorylation of PKA and eNOS, the effect of which was reversed by ALDH2. Moreover, 4-HNE mimicked doxorubicin-induced cardiomyocyte anomalies, the effect of which was ablated by SA13353. Taken together, our results suggested that ALDH2 may rescue against doxorubicin cardiac toxicity possibly through a TRPV1-mediated protection of mitochondrial integrity.

01 Jun 2014·European Journal of PharmacologyQ3 · MEDICINE

Activation of the TRPV1 channel attenuates N-methyl-d-aspartic acid-induced neuronal injury in the rat retina

Q3 · MEDICINE

Article

Author: Nakahara, Tsutomu ; Sekiya, Haruna ; Watanabe, Akihiro ; Mori, Asami ; Kuroki, Taiyo ; Sakamoto, Kenji ; Ito, Hiroko ; Okuno, Yui ; Ishii, Kunio ; Mizuta, Aya ; Sagawa, Tomonori

Capsaicin, a transient receptor potential vanilloid type1 (TRPV1) agonist, has been reported to protect against ischemia-reperfusion injury in various organs, including the brain, heart, and kidney, whereas activation of TRPV1 was also reported to contribute to neurodegeneration, including pressure-induced retinal ganglion cell death in vitro. We histologically investigated the effects of capsaicin and SA13353, TRPV1 agonists, on retinal injury induced by intravitreal N-methyl-d-aspartic acid (NMDA; 200 nmol/eye) in rats in vivo. Under ketamine/xylazine anesthesia, male Sprague-Dawley rats were subjected to intravitreal NMDA injection. Capsaicin (5.0 nmol/eye) was intravitreally admianeously with NMDA injection. SA13353 (10mg/kg) was intraperitoneally administered 15 min before NMDA injection. Morphometric evaluation at 7 days after NMDA injection showed that intravitreal NMDA injection resulted in ganglion cell loss. Capsaicin and SA13353 almost completely prevented this damage. Treatment with capsazepine (TRPV1 antagonist, 0.5 nmol/eye), CGRP (8-37) (calcitonin gene-related peptide (CGRP) receptor antagonist, 0.5 pmol/eye), or RP67580 (tachykinin NK1 receptor antagonist, 0.5 nmol/eye) almost completely negated the protective effect of capsaicin in the NMDA-injected rats. Seven days after intravitreal NMDA injection, the cell number of retinal ganglion cell was significantly smaller than in the eye that had received capsaicin in B6.Cg-TgN(Thy1-CFP)23Jrs/J transgenic mice that express the enhanced cyan fluorescent protein in retinal ganglion cells in the retina. These results suggested that activation of TRPV1 protects retinal neurons from the injury induced by intravitreal NMDA in rats in vivo. Activation of CGRP and tachykinin NK1 receptors is possibly involved in underlying protective mechanisms.

01 Apr 2012·Journal of Molecular Cell BiologyQ2 · BIOLOGY

Cardiac-specific knockout of ETA receptor mitigates low ambient temperature-induced cardiac hypertrophy and contractile dysfunction

Q2 · BIOLOGY

ArticleOA

Author: Dong, Feng ; Yanagisawa, Masashi ; Li, Linlin ; Hua, Yinan ; Zhang, Yingmei ; Ren, Jun ; Nunn, Jennifer M.

AbstractCold exposure is associated with oxidative stress and cardiac dysfunction. The endothelin (ET) system, which plays a key role in myocardial homeostasis, may participate in cold exposure-induced cardiovascular dysfunction. This study was designed to examine the role of ET-1 in cold stress-induced cardiac geometric and contractile responses. Wild-type (WT) and ETA receptor knockout (ETAKO) mice were assigned to normal or cold exposure (4°C) environment for 2 and 5 weeks prior to evaluation of cardiac geometry, contractile, and intracellular Ca2+ properties. Levels of the temperature sensor transient receptor potential vanilloid (TRPV1), mitochondrial proteins for biogenesis and oxidative phosphorylation, including UCP2, HSP90, and PGC1α were evaluated. Cold stress triggered cardiac hypertrophy, depressed myocardial contractile capacity, including fractional shortening, peak shortening, and maximal velocity of shortening/relengthening, reduced intracellular Ca2+ release, prolonged intracellular Ca2+ decay and relengthening duration, generation of ROS and superoxide, as well as apoptosis, the effects of which were blunted by ETAKO. Western blotting revealed downregulated TRPV1 and PGC1α as well as upregulated UCP2 and activation of GSK3β, GATA4, and CREB in cold-stressed WT mouse hearts, which were obliterated by ETAKO. Levels of HSP90, an essential regulator for thermotolerance, were unchanged. The TRPV1 agonist SA13353 attenuated whereas TRPV1 antagonist capsazepine mimicked cold stress- or ET-1-induced cardiac anomalies. The GSK3β inhibitor SB216763 ablated cold stress-induced cardiac contractile (but not remodeling) changes and ET-1-induced TRPV1 downregulation. These data suggest that ETAKO protects against cold exposure-induced cardiac remodeling and dysfunction mediated through TRPV1 and mitochondrial function.

100 Deals associated with SA-13353

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetic macular oedema	Phase 2	JP	-	-
Diabetic macular oedema	Phase 2	-	AYUMI Pharmaceutical Corp.Startup	-
Diabetic macular oedema	Phase 2	-	Santen SAS	-
Rheumatoid Arthritis	Phase 2	-	Santen SAS	-
Rheumatoid Arthritis	Phase 2	-	AYUMI Pharmaceutical Corp.Startup	-
Rheumatoid Arthritis	Phase 2	JP	-	-

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