Henry Ford Health System Henry Ford Health System Scholarly Commons Hypertension and Vascular Research Articles Hypertension and Vascular Research 10-28-2020 Role of Kinins in Hypertension and Heart Failure Suhail Hamid Imane A. Rhaleb Kamal M. Kassem Nour-Eddine Rhaleb Follow this and additional works at: https://scholarlycommons.henryford.com/hypertension_articles pharmaceuticals Review Role of Kinins in Hypertension and Heart Failure Suhail Hamid 1, Imane A. Rhaleb 1, Kamal M. Kassem 2 and Nour-Eddine Rhaleb 1,3,* 1 Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA; [email protected] (S.H.); [email protected] (I.A.R.) 2 Division of Cardiology, Department of Internal Medicine, University of Louisville Medical Center, Louisville, KY 40202, USA; [email protected] 3 Department of Physiology, Wayne State University, Detroit, MI 48201, USA * Correspondence: [email protected]; Tel.: +1-313-432-7314 Received: 21 September 2020; Accepted: 15 October 2020; Published: 28 October 2020 Abstract: The kallikrein–kinin system (KKS) is proposed to act as a counter regulatory system against the vasopressor hormonal systems such as the renin-angiotensin system (RAS), aldosterone, and catecholamines. Evidence exists that supports the idea that the KKS is not only critical to blood pressure but may also oppose target organ damage. Kinins are generated from kininogens by tissue and plasma kallikreins. The putative role of kinins in the pathogenesis of hypertension is discussed based on human mutation cases on the KKS or rats with spontaneous mutation in the kininogen gene sequence and mouse models in which the gene expressing only one of the components of the KKS has been deleted or over-expressed. Some of the effects of kinins are mediated via activation of the B2 and/or B1 receptor and downstream signaling such as eicosanoids, nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and/or tissue plasminogen activator (T-PA). The role of kinins in blood pressure regulation at normal or under hypertension conditions remains debatable due to contradictory reports from various laboratories. Nevertheless, published reports are consistent on the protective and mediating roles of kinins against ischemia and cardiac preconditioning; reports also demonstrate the roles of kinins in the cardiovascular protective effects of the angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor blockers (ARBs). Keywords: kallikrein–kinin system; bradykinin; B1 and B2 receptors; angiotensin-converting enzyme; angiotensin receptor blockers; hypertension; myocardial infarction; mice 1. Kallikrein–Kinin System Plasma and tissue kallikreins are potent enzymes that generate kinins by hydrolyzing kininogens, which circulate at high concentrations in plasma (Figure1). Kinins are rapidly destroyed by kininases [ 1]. Plasma kallikrein, also known as Fletcher factor, is expressed mainly in the liver; in plasma it is found in the zymogen form (pre-kallikrein) and differs from glandular kallikrein not only biochemically but also immunologically and functionally. Plasma kallikrein is encoded by a single gene, KLKB1. Some polymorphisms of this gene are associated with end-stage renal disease and hypertension [4–6]. Plasma kallikrein preferentially releases bradykinin (BK) from high-molecular-weight kininogen (HMWK), also known as the Fitzgerald factor. Together with HMWK and Hageman factor (factor XII), plasma kallikrein is involved in coagulation and fibrinolysis. The plasma kallikrein–HMWK system, acting through the release of BK, could be involved in the local regulation of blood flow and in mediating some of the effects of angiotensin-converting enzyme (ACE) inhibitors. On the other hand, patients with a congenital deficiency of plasma HMWK (Fitzgerald trait) have normal amounts of kinins in their blood [7] (For a review of the plasma kallikrein–HMWK system, see [8–11]). Pharmaceuticals 2020, 13, 347; doi:10.3390/ph13110347 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2020, 13, 347 2 of 25 Pharmaceuticals 2020, 13, x FOR PEER REVIEW 2 of 27 Figure 1. Site of kininogen cleavage (solid arrows) by the main kininogenases (glandular and plasma kallikrein). The The broken broken arrows arrows indicate indicate sites sites of of kinin cleavage by kininases (kininase I, I, kininase II, neutral endopeptidases 24.11 and 24.15 and aminopeptidases). (Modified(Modified after Rhaleb et al. [[2,2,33]])) 1.1. Tissue (Glandular) Kallikrein Plasma kallikrein, also known as Fletcher factor, is expressed mainly in the liver; in plasma it is foundKallikreins in the zymogen (KLK) are form serine (pre proteases-kallikrein) with veryand highdiffers homology from andglandular are expressed kallikrein by genesnot only that arebiochemically compactly but clustered also immunolo and arrangedgically in tandemand functionally. on the same Plasma chromosome. kallikrein Theis encoded kallikrein by family a single is estimatedgene, KLKB1. to contain Some atpolymorphisms least 15 genes inof humans,this gene 20 are in associated rats and 23–30 with in end mice-stage [12]. renal However, disease not and all thesehypertension proteases [4 generate–6]. Plasma kinins, despitekallikrein their preferentially highly homologous releases amino bradykinin acid composition; (BK) rather,from theyhigh- actmolecula on diffrerent-weight substrates kininogen and (HMWK), are expressed also in known different as tissues the Fitzgerald [13–16]. KLK1 factor. (tissue Together kallikrein) with isHMWK encoded and by aHageman single gene factor containing (factor five XII), exons plasma and four kallikrein introns. is While involved the KLK1 in genecoagulation is expressed and infibrinolysis. the submandibular The plasma gland, kallikrein pancreas–HMWK and kidney, system, small acting amounts through of kallikrein the release mRNA of wereBK, could detected be ininvolved the heart, in the vascular local regulation tissue and of adrenal blood glands flow and (PCR) in mediating [17,18]. Kallikrein some of andthe effects similar of enzymes angiotensin have- beenconverting found enzyme in the arteries (ACE) andinhibitors. veins [ 19On], heartthe other [20], hand, brain [patients21], spleen with [22 a], congenital adrenal glands deficiency [23] and of bloodplasma cells HMWK [18]; they(Fitzgerald have also trait) been have observed normal inamounts the pituitary of kinins gland in their [24,25 blood], pancreas [7]. (For [26 ],a review large and of smallthe plasma intestines kallikrein [27,28–],HMWK and salivary system, and see sweat [8–11] glands.) [29] along with their exocrine secretions. Tissue kallikrein immunoreactivity can be found in plasma, primarily in the inactive form; only a small portion remains1.1. Tissue active (Glandular) [30–33]. Kallikrein Approximately 50% of urinary kallikrein is found to be inactive (zymogen) in humans [34] and rabbits [35], while in rats most of it is active [36]. Tissue kallikrein can release kinins Kallikreins (KLK) are serine proteases with very high homology and are expressed by genes that from low-molecular-weight kininogen (LMWK) and HMWK. In humans, KLK1 releases lys-bradykinin are compactly clustered and arranged in tandem on the same chromosome. The kallikrein family is (kallidin; KD), whereas in rodents it releases bradykinin [37,38]. estimated to contain at least 15 genes in humans, 20 in rats and 23–30 in mice [12]. However, not all 1.2.these Kininogens proteases or generate Kallikrein kinins, Substrates despite their highly homologous amino acid composition; rather, they act on different substrates and are expressed in different tissues [13–16]. KLK1 (tissue kallikrein) is encodedKininogens by a si orngle kallikrein gene containing substrates five are theexons precursors and four of introns. kinins. InWhile plasma the thereKLK1 are gene two is main expressed forms, LMWKin the submandibular and HMWK. Interestingly, gland, pancreas the and human kidney, genome small contains amounts a single of kallikrein copy of mRNA the kininogen were detected family, whereasin the heart, three vascular copies exist tissue in theand rat adrenal (one encoding glands (PCR) K-kininogen [17,18] and. Kallikrein two encoding and similar T-kininogen, enzymes and have two homologousbeen found in kininogen the arteries genes and in veins the mouse[19], heart genome, [20], mkng1brain [21] and, spleen mkng2 [22] [39,, 40adrenal]. In rats, glands T-kininogen, [23] and theblood major cells kininogen, [18]; they releaseshave also T-kinins been observed (Ile-Ser-bradykinin) in the pituitary when gland incubated [24,25] with, pancreas trypsin [26] but, large not with and tissuesmall intestines or plasma [27, kallikrein.28], and T-kinin,salivary actingand sweat via B 2glandsreceptors, [29] along is one with of the their main exocrine acute reactants secretions. of inflammationTissue kallikrein [41 –immunoreactivity44]. HMWK is involved can be infound the early in plasma, stages primarily of surface-activated in the inactive coagulation form; only (intrinsic a small coagulationportion remains pathway) active [8 ,[3010,–4533]].. Approximately 50% of urinary kallikrein is found to be inactive (zymogen) in humans [34] and rabbits [35], while in rats most of it is active [36]. Tissue kallikrein can release kinins from low-molecular-weight kininogen (LMWK) and HMWK. In humans, KLK1 releases lys-bradykinin (kallidin; KD), whereas in rodents it releases bradykinin [37,38]. Pharmaceuticals 2020, 13, x FOR PEER REVIEW 3 of 27 1.2.