Alda-1, an activator of ALDH2, ameliorates Achilles tendinopathy in cellular and mouse models

Achilles tendinopathy has a high re-injury rate and poor prognosis. Development of effective therapy for Achilles tendinopathy is important. Excessive accumulation of ROS and resulting oxidative stress are believed to cause tendinopathy. Overproduction of hydrogen peroxide (H₂O₂), the most common ROS, could lead to the tendinopathy by causing oxidative damage, activation of endoplasmic reticulum (ER) stress and apoptotic death of tenocytes. Activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) is expected to alleviate oxidative stress and ER stress. Alda-1 is a selective and potent activator of ALDH2. In this study, we examined the cytoprotective benefit of Alda-1, an activator of ALDH2, on H₂O₂-induced Achilles tendinopathy in cellular and mouse models. We prepared cellular and mouse models of Achilles tendinopathy by treating cultured Achilles tenocytes and Achilles tendons with oxidative stressor H₂O₂. Subsequently, we studied the protective benefit of Alda-1 on H₂O₂-induced Achilles tendinopathy. Alda-1 pretreatment attenuated H₂O₂-induced cell death of cultured Achilles tenocytes. Treatment of Alda-1 prevented H₂O₂-induced oxidative stress and depolarization of mitochondrial membrane potential in tenocytes. Application of Alda-1 attenuated H₂O₂-triggered mitochondria- and ER stress-mediated apoptotic cascades in cultured tenocytes. Alda-1 treatment ameliorated the severity of H₂O₂-induced Achilles tendinopathy in vivo by preventing H₂O₂-induced pathological histological features of Achilles tendons, apoptotic death of Achilles tenocytes and upregulated expression of inflammatory cytokines IL-1β and TNF-α. Our results provide the evidence that ALDH2 activator Alda-1 ameliorates H₂O₂-induced Achilles tendinopathy. Alda-1 could be used for preventing and treating Achilles tendinopathy.