Palmitate-induced cardiac lipotoxicity is relieved by Quercetin and its novel acetylated derivative Q2 through inhibition of oxidative stress and inflammation

The association between obesity and cardiovascular risk is well established. The excess of triglycerides and circulating free fatty acids, in particular palmitate (PA), in the heart leads to cardiac lipotoxicity, a phenomenon that plays a key role in obesity-related cardiovascular complications. Over the last few years, natural compounds, such as the flavonoid quercetin (QUE), emerged as beneficial and cardioprotective agents in various cardio-metabolic diseases. Here, we investigated the beneficial role of QUE and its derivative Q2 - in which all hydroxyl groups were replaced by acetyl groups to improve bioavailability and stability - against cardiac lipotoxicity in vitro. In particular, H9c2 cardiomyocytes were pre-treated with QUE or Q2 and then exposed to PA to mimic cardiac lipotoxicity. Our results showed that both QUE and Q2 significantly counteracted PA-dependent cell death, although QUE was effective at lower concentrations (50 nM) compared with Q2, which was effective at 250 nM. During PA exposure QUE reduced the release of lactate dehydrogenase (LDH) and the accumulation of intracellular lipid droplets, while protectingcardiomyocytes from PA-induced oxidative stress by counteracting the generation of malondialdehyde (MDA), protein carbonyl groups and intracellular ROS, and by enhancing the activity of the key antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). Moreover, QUE significantly attenuated PA-induced inflammatory response by reducing the release of the pro-inflammatory cytokines interleukin 1-β (IL-1β) and tumour necrosis factor- α (TNF-α). Similar to QUE, the pre-treatment with Q2 also induced a significant reduction of intracellular lipid droplets, LDH and MDA, improved SOD activity, and attenuated the release of IL-1β and TNF-α. Our results provide new evidence on the beneficial role of QUE and Q2 as potential therapeutic agents for counteracting lipotoxicity in the heart, that occurs during obesity and metabolic diseases.