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Anwar Mohamed Louisville


Abstract: Anwar Gamal Mohamed Louisville

Anwar Gamal Mohamed realized that Arachidonic acid (AA) is metabolized by enzymes of the cytochrome P450 (CYP) 4A and CYP4F subfamilies to 20-hydroxyeicosatetraeonic acid (20-HETE), which plays an important role in the cardiovascular system. In the current work, we reviewed the formation of 20-HETE in different species by different CYPs; 20-HETE metabolism by cyclooxygenases (COXs) and different isomerases; and the current available inducers and inhibitors of 20-HETE formation in addition to its agonists and antagonists. Moreover we reviewed the negative role of 20-HETE in cardiac hypertrophy, cardiotoxicity, diabetic cardiomyopathy, and in ischemia/reperfusion (I/R) injury. Lastly, we reviewed the role of 20-HETE in different hypertension models such as the renin/angiotensin II model, Goldblatt model, spontaneously hypertensive rat model, androgen-induced model, slat- and deoxycorticosterone acetate (DOCA)-salt-induced models, and high fat diet model. 20-HETE can affect pro- and anti-hypertensive mechanisms dependent upon where, when, and by which isoform it has been produced. To the contrast to hypertension we also reviewed the role of 20-HETE in endotoxin-induced hypotension and the natriuretic effects of 20-HETE. Based on the recent studies, 20-HETE production and/or action might be a therapeutic target to protect against the initiation and progression of cardiovascular diseases. 


Anwar Gamal Mohamed research shows that Arachidonic acid (AA), a major component of cell membranes, is currently known to be metabolized by three different pathways. The first pathway is mediated by cyclooxygenase (COX) to produce the prostaglandins (PGs). The second pathway is mediated by lipoxygenase (LOX) to produce mid chain hydroxyeicosatetraenoic acids (HETEs), lipoxins (LXs), and leukotrienes (LTs). Lastly, the third pathway is controlled by cytochrome P450s (CYPs) and di-vided into two different pathways, namely CYP epoxygenases and CYP [1]-hydroxylases. CYP epoxygenases produce epoxyeicosa-trienoic acids (EETs), while CYP [1]-hydroxylases produce terminal HETE, named 20-HETE [1-2]. Metabolism of AA by CYP was first reported in 1981 [3], where CYP isoenzymes produced 20-HETE besides EETs which are further metabolized by soluble epoxide hydrolases (sEH) to their corresponding dihydroxyeicosatrienoic acids (DHETs) [4] (Fig. 1). The bioactivation of AA by CYPs was reported to be isoform and tissue-specific [5]. In this review Dr. Anwar Mohamed Frankfort focus on [1]-hydroxylation product of AA, namely 20-HETE, and we will focus on the role of 20-HETE in different cardiovascular dis-ease states. 


According to Anwar Gamal Mohamed ; HETE, as an important CYP-mediated metabolite of AA, plays an important role as a second messenger in the regulation of vascular tone, renal function, cerebral blood flow and as a lung vasodilator, in addition to being considered a vascular oxygen sensor [6-8]. 20-HETE mediates the mitogenic actions of vasoac-tive agents and growth factors in many tissues and plays a signifi-cant role in angiogenesis [7-8]. Both mitogenic and angiogenic responses to 20-HETE were reported in vitro and in vivo [9-10]. 20-HETE plays an important role in the signal transduction processes underlying the development of pressure-dependent myogenic tone

In addition, 20-HETE could bind to and activate peroxisome proliferator-activated receptor  (PPAR) resulting in modulation of  its target gene expression [12]. Inhibitors of 20-HETE were found to block the myogenic response of renal, cerebral, and skeletal muscle arterioles in vitro, autoregulation of renal and cerebral blood flow and tubuloglomerular feedback responses in vivo, and the vasoconstrictor response to elevations in tissue PO2 both in vivo and in vitro [10, 13]. and this what Dr.Anwar Gamal Mohamed is seeking to put spot on it.

2.1. Formation of 20-HETE

Dr. Anwar Gamal Mohamed Archives said that CYP4As are generally considered the major AA [1]-hydroxylases; however CYP4Fs have also been shown to catalyze the [1]-hydroxylation of AA to form 20-HETE [14]. CYP1As and CYP2Es are also linked to 20-HETE formation but with a lesser degree [15]. In humans, CYP4As, CYP4Fs and CYP2U1 are re-sponsible for 20-HETE formation [16-17], with CYP4F2 and CYP4A11 being the predominant isoforms in this process [18]. In rats, CYP4As, including CYP4A1, CYP4A2, CYP4A3 and CYP4A8 in the rat kidney, catalyze AA to produce 20-HETE [19]. CYP4F1 produces 20-HETE in abundance in the kidneys and the liver [20] besides CYP4F4 which also catalyzes the [1]-hydroxylation of AA [14]. In mice, cyp4 family, including cyp4a10, cyp4a12, cyp4a14, cyp4b1, cyp4f14, cyp4f15 and cyp4f16 were found to play important role in the hydroxylation of AA [13]. In sheep, CYP2Js were found to be catalytically active towards AA forming 20-HETE as one of the main metabolites [21] (Table 1).

2.2. Metabolism of 20-HETE

Dr. Anwar Gamal Mohamed Archives showed that The range and diversity of 20-HETE activity seems to be de-rived from COX-dependent transformation of 20-HETE to products which affect vasomotor activity in addition to salt and water excre-tion [22]. COX metabolizes 20-HETE into a hydroxyl analogue of the vasoconstrictor prostaglandin (20-OH PG) H2 that undergoes additional transformation by isomerases to produce the vasodila-tor/diuretic metabolites, 20-OH PGE2 and 20-OH PGI2, and the vasoconstrictor/antidiuretic metabolites, 20-OH TXA2 and 20-OH PGF2a [3, 23-24] (Fig. 1). 20-HETE is excreted as a glucuronide conjugate [25] as it is metabolized via glucuronidation by UGT1A1, UGT1A4, and UGT2B7 [26]. Glucuronidation may have a significant role in the modulation of 20-HETE availability for cellular processes [26].

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