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Cytochromes P450, Cardiovascular Homeostasis and Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Chin Eng Ong, Amelia Dong, Boon Hooi Tan, Yan Pan
The impaired endothelial function and dysregulated coronary blood flow in CAD eventually contribute to the onset and progression of atherosclerosis and thrombosis (Kinlay et al., 2001). Substantial evidence has demonstrated that CYP-generated EETs serve as endothelial-derived hyperpolarizing factor (EDHF) in the coronary circulation (Campbell et al., 1996). EDHF activates the large-conductance calcium-activated potassium (BK) channels and the Na+-K+-ATPase, and therefore induces hyperpolarization of vascular smooth muscle cells. This results in smooth muscle relaxation, therefore reducing contractile force and oxygen utilization of the muscle, leading to vasodilation (Fleming, 2014; Schinzari et al., 2017). Plasma concentrations of EETs have been demonstrated to be elevated in patients with CAD compared to healthy controls (Theken et al., 2012). It has been suggested that EETs may become up-regulated to compensate for the overall endothelial dysfunction. The key role of CYPs and EDHF is further supported from their expression modulation by the dihydropyridine calcium channel blocker nifedipine. This drug was able to up-regulate expression of CYP2C, but not 2J or 2B, in coronary endothelium. Furthermore, it stimulated EET biosynthesis and potentiated hyperpolarization of coronary artery smooth muscle cells mediated through bradykinin and EDHF (Fisslthaler et al., 2000). The cardioprotective role of EETs has also been demonstrated in transgenic animal model. Transgenic mice with selective overexpression of CYP 2J2 in cardiomyocyte exhibited better post-ischemic recovery of left ventricular function after prolonged ischemia. This protective effect was however abolished in the presence of the CYP epoxygenase inhibitor N-methylsulfonyl-6-(2-proparglyloxphenyl) hexamide (Seubert et al., 2004). This was further supported by studies in both adult mongrel dogs and rats (Gross et al., 2011) using the same inhibitor. These findings are in agreement with the reduced formation of atherosclerotic injury in apoplipoprotein E knockout mice observed following sEH inhibition (Ulu et al., 2008). Some other studies demonstrated beneficial effects of EETs on long-term endpoints post-infarction. A study using male rats treated with an sHE inhibitor, GSK2188931B (N-(4-bromo-2-[(trifluoromethyl)oxy]phenyl)methyl)-1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-4 piperidine carboxamide) immediately following permanent ligation of the left anterior descending coronary artery exhibited anti-remodeling effects such as reduced hypertrophy, lower inflammation, decreased ventricular fibrosis and sustained systolic function 5 weeks post-infarction (Kompa et al., 2013). More recently, in vivo studies demonstrated that a selective sHE inhibitor, 4-[[trans-4 [[(tricyclo [3.3.1.13,7]dec-1-ylamino)carbonyl] amino] cyclohexyl]oxy]-benzoic acid (t-AUCB) conferred protection against ischemic injury by preserving cardiomyocyte function and maintaining mitochondrial efficiency (Akhnokh et al., 2016). In another study, improved coronary endothelial function and attenuated cardiac remodeling and diastolic dysfunction were observed in obese insulin-resistant mice following treatment with t-AUCB (Roche et al., 2015).
Physiological and pathophysiological implications of hydrogen sulfide: a persuasion to change the fate of the dangerous molecule
Published in Journal of the Chinese Advanced Materials Society, 2018
Jan Mohammad Mir, Ram Charitra Maurya
Subsequent to EDRF was identified as NO, several discrepancies were found. For example, EDRF relaxes vascular smooth muscle and hyperpolarizes the membrane potential, while NO does not induce hyperpolarization.[106] These discrepancies suggest that EDRF contains additional factors to NO. One of these factors has been designated as endothelium-derived hyperpolarizing factor (EDHF), whose candidates [107] include metabolites of arachidonic acid, such as, prostacyclin and epoxyeicosatrienoic acids, H2O2, and K+. 3MST, along with CAT, has recently been found in vascular endothelium and produces H2S in the presence of cysteine and α-ketoglutarate.[108, 109] Although it is controversial, CSE has also been proposed to be localized to endothelial cells.[110] Since H2S can be produced and released from the endothelium, similar to EDHF, and because H2S hyperpolarizes vascular smooth muscle by activating ATP-sensitive K+ channels, it has been proposed that H2S may be EDHF. However, there are some discrepancies in the characteristics between H2S and EDHF. Changes in membrane potential induced by EDHF are resistant to the ATP-sensitive K+ channel blocker, glibenclamide.[111, 112] In contrast, relaxation of vascular smooth muscle in the mesenteric bed, which is mediated predominantly by EDHF, is abolished by apamine, a blocker of Ca2+-activated K+ channels.[113] These observations suggest that H2S may not be EDHF. Thus, further studies are required to determine whether or not H2S is a component of EDRFs.