The novel H 2 S-donor 4-carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoK ATP channels and reduction of oxidative stress

Abstract

a b s t r a c tThe endogenous gasotransmitter hydrogen sulphide (H 2 S) is an important regulator of the cardiovascular system, particularly of myocardial function. Moreover, H 2 S exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury, and is considered an important mediator of "ischemic preconditioning", through activation of mitochondrial potassium channels, reduction of oxidative stress, activation of the endogenous "anti-oxidant machinery" and limitation of inflammatory responses. Accordingly, H 2 S-donors, i.e. pro-drugs able to generate exogenous H 2 S, are viewed as promising therapeutic agents for a number of cardiovascular diseases. The novel H 2 S-donor 4-carboxy phenylisothiocyanate (4CPI), whose vasorelaxing effects were recently reported, was tested here in different experimental models of myocardial I/R.In Langendorff-perfused rat hearts subjected to I/R, 4CPI significantly improved the post-ischemic recovery of myocardial functional parameters and limited tissue injury. These effects were antagonized by 5-hydroxydecanoic acid (a blocker of mitoK ATP channels). Moreover, 4CPI inhibited the formation of reactive oxygen species. We found the whole battery of H 2 S-producing enzymes to be present in myocardial tissue: cystathionine ␥-lyase (CSE), cystathionine ␤-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST). Notably, 4CPI down-regulated the post-ischemic expression of CSE.In Langendorff-perfused mouse hearts, 4CPI reduced the post-ischemic release of norepinephrine and the incidence of ventricular arrhythmias. In both rat and mouse hearts, 4CPI did not affect the degranulation of resident mast cells.In isolated rat cardiac mitochondria, 4CPI partially depolarized the mitochondrial membrane potential; this effect was antagonized by ATP (i.e., the physiological inhibitor of K ATP channels). Moreover, 4CPI abrogated calcium uptake in the mitochondrial matrix.Finally, in an in vivo model of acute myocardial infarction in rats, 4CPI significantly decreased I/Rinduced tissue injury.In conclusion, H 2 S-donors, and in particular isothiocyanate-based H2S-releasing drugs like 4CPI, can actually be considered a suitable pharmacological option in anti-ischemic therapy.

Kinetic Insights into Hydrogen Sulfide Delivery from Caged-Carbonyl Sulfide Isomeric Donor Platforms

“…78 Although aryl isothiocyanates are known H 2 S donors, the H 2 S release from these compounds less efficient than from the OA-PeroxyTCM core and thus would be expected to reduce the overall rate of H 2 S formation. 79–80 H 2 S Releasing efficiency was calculated by using a NaSH calibration curve. The low efficiency of H 2 S release EWG-containing donors, especially for OA-PeroxyTCM-6 , highlighting a limitation of including highly electron withdrawing moieties on thiocarbamate-based donor motifs.…”

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

“…After stimulation with 100 ng·ml −1 of DNP‐HSA Ag for 30 min, supernatants were collected separately to determine β‐hexosaminidase levels. LAD2 cells were treated with different concentrations of tozasertib for 1 hr, incubated with PMACI (10‐μM PMA and 500‐nM CI) for 30 min, and the supernatant was collected to determine β‐hexosaminidase levels (Park et al, 2018; Testai et al, 2016; Wang et al, 2017).…”

Mitochondrialne kanały potasowe: podsumowanie

“…The presence of Kv channels in mitochondria is well documented for Kv1.3 [20][21][22][23][24], but the presence of Kv7.4 was recently reported [25].…”

“…Unfortunately, little is known about the effects of H 2 S on the activity of mitochondrial potassium channels. In 2016, Testai et al found that 4-carboxyphenyl isothiocyanate (4CPI), used as an H 2 S donor in Langendorff-perfused rat hearts subjected to ischemia/reperfusion, enhanced the recovery of myocardial functional parameters and reduced tissue injury that was antagonized by 5-HD [25]. 4-CPI was also added to the isolated rat heart mitochondria, resulting in the depolarization of the mitochondrial membrane potential that was abrogated by the addition of ATP, which is a physiological blocker of mitoK ATP [25].…”