# Cardiac injury elicited by sub-chronic hookah smoke inhalation, and the alleviating effect of procysteine, 2-oxo-(4R)-4-thiazolidinecarboxylic acid, in BALB/c mice

## TL;DR

This study shows that procysteine (OTC) protects the heart from damage caused by hookah smoke by reducing inflammation and oxidative stress in mice.

## Contribution

The novel finding is that OTC mitigates hookah smoke-induced cardiac injury through specific molecular mechanisms including Nrf2 activation and NF-κB inhibition.

## Key findings

- OTC reduced oxidative stress, inflammation, DNA damage, and apoptosis in the heart caused by hookah smoke.
- OTC suppressed NLRP3 inflammasome and IL-1β activation, inhibited NF-κB, and restored sirtuin-1 expression.
- OTC enhanced Nrf2 expression in the heart under hookah smoke exposure with no histological changes observed.

## Abstract

Hookah smoke (HS) inhalation is known to induce cardiovascular dysfunction, including oxidative stress and inflammation. The procysteine, 2-oxo-(4R)-4-thiazolidinecarboxylic acid (OTC) is a prodrug of cysteine, a precursor of glutathione, which is a major intracellular antioxidant. This study aimed to evaluate the possible cardioprotective effects of OTC against HS inhalation-induced cardiac injury in mice. The animals were exposed to HS for 30 min per day, five days per week, for one month, while control mice were exposed to normal air. OTC was administered by gavage at a dose of 80 mg/kg 1 h before each exposure session. OTC prevented HS-induced increase in the concentrations of tumor necrosis factor α, interleukin (IL)-6 and galectin-3 in the heart tissue. HS exposure augmented the levels of markers of oxidative stress and adhesion molecules. The latter effects were significantly abrogated by OTC treatment. Likewise, the cardiac DNA damage and apoptosis triggered by HS inhalation were significantly prevented in mice treated with OTC. The concentrations of NLRP3 inflammasome and IL-1β in the hearts of mice exposed to HS were significantly augmented, and OTC treatment significantly abated this effect. Moreover, while the cardiac expression of phosphorylated nuclear factor κB (NF-κB) was increased, that of sirtuin-1 was significantly decreased by HS inhalation. Both effects were significantly mitigated by OTC administration. Furthermore, HS inhalation induced an elevation in the concentrations of mammalian targets of rapamycin and nuclear factor erythroid-derived 2-like 2 (Nrf2) expression in the heart, and this effect was significantly potentiated in the OTC + HS group. Despite these molecular and biochemical alterations, no detectable differences in cardiac histology were observed among the experimental groups. Collectively, these findings demonstrate that OTC mitigates HS-induced cardiac injury by reducing oxidative stress, inflammation, DNA damage, and apoptosis through mechanisms that involve inhibition of NLRP3 inflammasome activation and NF-κB signaling, together with activation of sirtuin-1 and Nrf2 pathways.

Image 1

•Hookah smoke (HS) inhalation induces cardiac oxidative stress, inflammation, and molecular injury in mice.•OTC attenuates HS-induced inflammation, oxidative stress, DNA damage, and apoptosis in the heart.•OTC suppresses HS-induced NLRP3 inflammasome and IL-1β activation, inhibits NF-κB, and restores sirtuin-1 expression.•OTC enhances cardiac Nrf2 expression under HS exposure, with no detectable histological changes.•OTC confers cardioprotection against HS through antioxidant and anti-inflammatory mechanisms.

Hookah smoke (HS) inhalation induces cardiac oxidative stress, inflammation, and molecular injury in mice.

OTC attenuates HS-induced inflammation, oxidative stress, DNA damage, and apoptosis in the heart.

OTC suppresses HS-induced NLRP3 inflammasome and IL-1β activation, inhibits NF-κB, and restores sirtuin-1 expression.

OTC enhances cardiac Nrf2 expression under HS exposure, with no detectable histological changes.

OTC confers cardioprotection against HS through antioxidant and anti-inflammatory mechanisms.