Diallyl Trisulfide (DATS) Suppresses AGE-Induced Cardiomyocyte Apoptosis by Targeting ROS-Mediated PKCδ Activation

Abstract

Chronic high-glucose exposure results in the production of advanced glycation end-products (AGEs) leading to reactive oxygen species (ROS) generation, which contributes to the development of diabetic cardiomyopathy. PKCδ activation leading to ROS production and mitochondrial dysfunction involved in AGE-induced cardiomyocyte apoptosis was reported in our previous study. Diallyl trisulfide (DATS) is a natural cytoprotective compound under various stress conditions. In this study, the cardioprotective effect of DATS against rat streptozotocin (STZ)-induced diabetic mellitus (DM) and AGE-induced H9c2 cardiomyoblast cell/neonatal rat ventricular myocyte (NRVM) damage was assessed. We observed that DATS treatment led to a dose-dependent increase in cell viability and decreased levels of ROS, inhibition of PKCδ activation, and recuded apoptosis-related proteins. Most importantly, DATS reduced PKCδ mitochondrial translocation induced by AGE. However, apoptosis was not inhibited by DATS in cells transfected with PKCδ-wild type (WT). Inhibition of PKCδ by PKCδ-kinase-deficient (KD) or rottlerin not only inhibited cardiac PKCδ activation but also attenuated cardiac cell apoptosis. Interestingly, overexpression of PKCδ-WT plasmids reversed the inhibitory effects of DATS on PKCδ activation and apoptosis in cardiac cells exposed to AGE, indicating that DATS may inhibit AGE-induced apoptosis by downregulating PKCδ activation. Similar results were observed in AGE-induced NRVM cells and STZ-treated DM rats following DATS administration. Taken together, our results suggested that DATS reduced AGE-induced cardiomyocyte apoptosis by eliminating ROS and downstream PKCδ signaling, suggesting that DATS has potential in diabetic cardiomyopathy (DCM) treatment.

A ROS-responsive, self-immolative and self-reporting hydrogen sulfide donor with multiple biological activities for the treatment of myocardial infarction

“…Nevertheless, inorganic salts, such as sodium hydrosulfide and sodium sulfide, are limited due to quick evaporation and loss of H 2 S after preparation in aqueous solutions, as well as rapid and almost instantaneous H 2 S release after in vivo injection. Alternatively, small molecular diallyl trisulfide (DATS) [ [15] , [16] , [17] ] and GYY-4137 [ 18 , 19 ], etc . [ 20 ] were synthesized and used in the studies on biological activities of H 2 S. However, H 2 S release from these donors are mostly based on a general hydrolysis mechanism, lacking of specificity or responsiveness to in vivo biological biomarkers.…”

PKCδ deficiency inhibits fetal development and is associated with heart elastic fiber hyperplasia and lung inflammation in adult PKCδ knockout mice

“…Moreover, continuous hyperglycemia is a common event in patients with type I and type II diabetes. It is reported that PKCδ is involved in advanced glycation end product-induced apoptosis produced by this hyperglycemic exposure [50,51]. Hence, it is expected that the mice produced in the present study will contribute to the elucidation of important functions of PKCδ and its role in various diseases.…”

Cardioprotective Potential of Garlic Oil and Its Active Constituent, Diallyl Disulphide, in Presence of Carvedilol during Chronic Isoprenaline Injection-Mediated Myocardial Necrosis in Rats

“…The antioxidant action of garlic oil is obviously due to organosulphurous compounds, but the exact mechanism is still not clear. A previous study employing DATS, another potent component of garlic, suggested cardioprotective effectiveness by lowering AGE-induced cardiomyocyte apoptosis by removing reactive oxygen species (ROS) and downstream PKCδ signaling [ 36 ]. Another interesting study explored the role of this polysulfide (DATS) and reported its effective mitigation of metabolic syndrome (MetS) as well as protective effects against ex vivo induced myocardial ischemia-reperfusion injury in MetS rats [ 37 ].…”