0
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Role of Kinins in Hypertension and Heart Failure

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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 B 2 and/or B 1 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).

          Related collections

          Most cited references236

          • Record: found
          • Abstract: found
          • Article: not found

          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The proximal origin of SARS-CoV-2

            To the Editor — Since the first reports of novel pneumonia (COVID-19) in Wuhan, Hubei province, China 1,2 , there has been considerable discussion on the origin of the causative virus, SARS-CoV-2 3 (also referred to as HCoV-19) 4 . Infections with SARS-CoV-2 are now widespread, and as of 11 March 2020, 121,564 cases have been confirmed in more than 110 countries, with 4,373 deaths 5 . SARS-CoV-2 is the seventh coronavirus known to infect humans; SARS-CoV, MERS-CoV and SARS-CoV-2 can cause severe disease, whereas HKU1, NL63, OC43 and 229E are associated with mild symptoms 6 . Here we review what can be deduced about the origin of SARS-CoV-2 from comparative analysis of genomic data. We offer a perspective on the notable features of the SARS-CoV-2 genome and discuss scenarios by which they could have arisen. Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus. Notable features of the SARS-CoV-2 genome Our comparison of alpha- and betacoronaviruses identifies two notable genomic features of SARS-CoV-2: (i) on the basis of structural studies 7–9 and biochemical experiments 1,9,10 , SARS-CoV-2 appears to be optimized for binding to the human receptor ACE2; and (ii) the spike protein of SARS-CoV-2 has a functional polybasic (furin) cleavage site at the S1–S2 boundary through the insertion of 12 nucleotides 8 , which additionally led to the predicted acquisition of three O-linked glycans around the site. 1. Mutations in the receptor-binding domain of SARS-CoV-2 The receptor-binding domain (RBD) in the spike protein is the most variable part of the coronavirus genome 1,2 . Six RBD amino acids have been shown to be critical for binding to ACE2 receptors and for determining the host range of SARS-CoV-like viruses 7 . With coordinates based on SARS-CoV, they are Y442, L472, N479, D480, T487 and Y4911, which correspond to L455, F486, Q493, S494, N501 and Y505 in SARS-CoV-2 7 . Five of these six residues differ between SARS-CoV-2 and SARS-CoV (Fig. 1a). On the basis of structural studies 7–9 and biochemical experiments 1,9,10 , SARS-CoV-2 seems to have an RBD that binds with high affinity to ACE2 from humans, ferrets, cats and other species with high receptor homology 7 . Fig. 1 Features of the spike protein in human SARS-CoV-2 and related coronaviruses. a, Mutations in contact residues of the SARS-CoV-2 spike protein. The spike protein of SARS-CoV-2 (red bar at top) was aligned against the most closely related SARS-CoV-like coronaviruses and SARS-CoV itself. Key residues in the spike protein that make contact to the ACE2 receptor are marked with blue boxes in both SARS-CoV-2 and related viruses, including SARS-CoV (Urbani strain). b, Acquisition of polybasic cleavage site and O-linked glycans. Both the polybasic cleavage site and the three adjacent predicted O-linked glycans are unique to SARS-CoV-2 and were not previously seen in lineage B betacoronaviruses. Sequences shown are from NCBI GenBank, accession codes MN908947, MN996532, AY278741, KY417146 and MK211376. The pangolin coronavirus sequences are a consensus generated from SRR10168377 and SRR10168378 (NCBI BioProject PRJNA573298) 29,30 . While the analyses above suggest that SARS-CoV-2 may bind human ACE2 with high affinity, computational analyses predict that the interaction is not ideal 7 and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding 7,11 . Thus, the high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2 that permits another optimal binding solution to arise. This is strong evidence that SARS-CoV-2 is not the product of purposeful manipulation. 2. Polybasic furin cleavage site and O-linked glycans The second notable feature of SARS-CoV-2 is a polybasic cleavage site (RRAR) at the junction of S1 and S2, the two subunits of the spike 8 (Fig. 1b). This allows effective cleavage by furin and other proteases and has a role in determining viral infectivity and host range 12 . In addition, a leading proline is also inserted at this site in SARS-CoV-2; thus, the inserted sequence is PRRA (Fig. 1b). The turn created by the proline is predicted to result in the addition of O-linked glycans to S673, T678 and S686, which flank the cleavage site and are unique to SARS-CoV-2 (Fig. 1b). Polybasic cleavage sites have not been observed in related ‘lineage B’ betacoronaviruses, although other human betacoronaviruses, including HKU1 (lineage A), have those sites and predicted O-linked glycans 13 . Given the level of genetic variation in the spike, it is likely that SARS-CoV-2-like viruses with partial or full polybasic cleavage sites will be discovered in other species. The functional consequence of the polybasic cleavage site in SARS-CoV-2 is unknown, and it will be important to determine its impact on transmissibility and pathogenesis in animal models. Experiments with SARS-CoV have shown that insertion of a furin cleavage site at the S1–S2 junction enhances cell–cell fusion without affecting viral entry 14 . In addition, efficient cleavage of the MERS-CoV spike enables MERS-like coronaviruses from bats to infect human cells 15 . In avian influenza viruses, rapid replication and transmission in highly dense chicken populations selects for the acquisition of polybasic cleavage sites in the hemagglutinin (HA) protein 16 , which serves a function similar to that of the coronavirus spike protein. Acquisition of polybasic cleavage sites in HA, by insertion or recombination, converts low-pathogenicity avian influenza viruses into highly pathogenic forms 16 . The acquisition of polybasic cleavage sites by HA has also been observed after repeated passage in cell culture or through animals 17 . The function of the predicted O-linked glycans is unclear, but they could create a ‘mucin-like domain’ that shields epitopes or key residues on the SARS-CoV-2 spike protein 18 . Several viruses utilize mucin-like domains as glycan shields involved immunoevasion 18 . Although prediction of O-linked glycosylation is robust, experimental studies are needed to determine if these sites are used in SARS-CoV-2. Theories of SARS-CoV-2 origins It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus. As noted above, the RBD of SARS-CoV-2 is optimized for binding to human ACE2 with an efficient solution different from those previously predicted 7,11 . Furthermore, if genetic manipulation had been performed, one of the several reverse-genetic systems available for betacoronaviruses would probably have been used 19 . However, the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone 20 . Instead, we propose two scenarios that can plausibly explain the origin of SARS-CoV-2: (i) natural selection in an animal host before zoonotic transfer; and (ii) natural selection in humans following zoonotic transfer. We also discuss whether selection during passage could have given rise to SARS-CoV-2. 1. Natural selection in an animal host before zoonotic transfer As many early cases of COVID-19 were linked to the Huanan market in Wuhan 1,2 , it is possible that an animal source was present at this location. Given the similarity of SARS-CoV-2 to bat SARS-CoV-like coronaviruses 2 , it is likely that bats serve as reservoir hosts for its progenitor. Although RaTG13, sampled from a Rhinolophus affinis bat 1 , is ~96% identical overall to SARS-CoV-2, its spike diverges in the RBD, which suggests that it may not bind efficiently to human ACE2 7 (Fig. 1a). Malayan pangolins (Manis javanica) illegally imported into Guangdong province contain coronaviruses similar to SARS-CoV-2 21 . Although the RaTG13 bat virus remains the closest to SARS-CoV-2 across the genome 1 , some pangolin coronaviruses exhibit strong similarity to SARS-CoV-2 in the RBD, including all six key RBD residues 21 (Fig. 1). This clearly shows that the SARS-CoV-2 spike protein optimized for binding to human-like ACE2 is the result of natural selection. Neither the bat betacoronaviruses nor the pangolin betacoronaviruses sampled thus far have polybasic cleavage sites. Although no animal coronavirus has been identified that is sufficiently similar to have served as the direct progenitor of SARS-CoV-2, the diversity of coronaviruses in bats and other species is massively undersampled. Mutations, insertions and deletions can occur near the S1–S2 junction of coronaviruses 22 , which shows that the polybasic cleavage site can arise by a natural evolutionary process. For a precursor virus to acquire both the polybasic cleavage site and mutations in the spike protein suitable for binding to human ACE2, an animal host would probably have to have a high population density (to allow natural selection to proceed efficiently) and an ACE2-encoding gene that is similar to the human ortholog. 2. Natural selection in humans following zoonotic transfer It is possible that a progenitor of SARS-CoV-2 jumped into humans, acquiring the genomic features described above through adaptation during undetected human-to-human transmission. Once acquired, these adaptations would enable the pandemic to take off and produce a sufficiently large cluster of cases to trigger the surveillance system that detected it 1,2 . All SARS-CoV-2 genomes sequenced so far have the genomic features described above and are thus derived from a common ancestor that had them too. The presence in pangolins of an RBD very similar to that of SARS-CoV-2 means that we can infer this was also probably in the virus that jumped to humans. This leaves the insertion of polybasic cleavage site to occur during human-to-human transmission. Estimates of the timing of the most recent common ancestor of SARS-CoV-2 made with current sequence data point to emergence of the virus in late November 2019 to early December 2019 23 , compatible with the earliest retrospectively confirmed cases 24 . Hence, this scenario presumes a period of unrecognized transmission in humans between the initial zoonotic event and the acquisition of the polybasic cleavage site. Sufficient opportunity could have arisen if there had been many prior zoonotic events that produced short chains of human-to-human transmission over an extended period. This is essentially the situation for MERS-CoV, for which all human cases are the result of repeated jumps of the virus from dromedary camels, producing single infections or short transmission chains that eventually resolve, with no adaptation to sustained transmission 25 . Studies of banked human samples could provide information on whether such cryptic spread has occurred. Retrospective serological studies could also be informative, and a few such studies have been conducted showing low-level exposures to SARS-CoV-like coronaviruses in certain areas of China 26 . Critically, however, these studies could not have distinguished whether exposures were due to prior infections with SARS-CoV, SARS-CoV-2 or other SARS-CoV-like coronaviruses. Further serological studies should be conducted to determine the extent of prior human exposure to SARS-CoV-2. 3. Selection during passage Basic research involving passage of bat SARS-CoV-like coronaviruses in cell culture and/or animal models has been ongoing for many years in biosafety level 2 laboratories across the world 27 , and there are documented instances of laboratory escapes of SARS-CoV 28 . We must therefore examine the possibility of an inadvertent laboratory release of SARS-CoV-2. In theory, it is possible that SARS-CoV-2 acquired RBD mutations (Fig. 1a) during adaptation to passage in cell culture, as has been observed in studies of SARS-CoV 11 . The finding of SARS-CoV-like coronaviruses from pangolins with nearly identical RBDs, however, provides a much stronger and more parsimonious explanation of how SARS-CoV-2 acquired these via recombination or mutation 19 . The acquisition of both the polybasic cleavage site and predicted O-linked glycans also argues against culture-based scenarios. New polybasic cleavage sites have been observed only after prolonged passage of low-pathogenicity avian influenza virus in vitro or in vivo 17 . Furthermore, a hypothetical generation of SARS-CoV-2 by cell culture or animal passage would have required prior isolation of a progenitor virus with very high genetic similarity, which has not been described. Subsequent generation of a polybasic cleavage site would have then required repeated passage in cell culture or animals with ACE2 receptors similar to those of humans, but such work has also not previously been described. Finally, the generation of the predicted O-linked glycans is also unlikely to have occurred due to cell-culture passage, as such features suggest the involvement of an immune system 18 . Conclusions In the midst of the global COVID-19 public-health emergency, it is reasonable to wonder why the origins of the pandemic matter. Detailed understanding of how an animal virus jumped species boundaries to infect humans so productively will help in the prevention of future zoonotic events. For example, if SARS-CoV-2 pre-adapted in another animal species, then there is the risk of future re-emergence events. In contrast, if the adaptive process occurred in humans, then even if repeated zoonotic transfers occur, they are unlikely to take off without the same series of mutations. In addition, identifying the closest viral relatives of SARS-CoV-2 circulating in animals will greatly assist studies of viral function. Indeed, the availability of the RaTG13 bat sequence helped reveal key RBD mutations and the polybasic cleavage site. The genomic features described here may explain in part the infectiousness and transmissibility of SARS-CoV-2 in humans. Although the evidence shows that SARS-CoV-2 is not a purposefully manipulated virus, it is currently impossible to prove or disprove the other theories of its origin described here. However, since we observed all notable SARS-CoV-2 features, including the optimized RBD and polybasic cleavage site, in related coronaviruses in nature, we do not believe that any type of laboratory-based scenario is plausible. More scientific data could swing the balance of evidence to favor one hypothesis over another. Obtaining related viral sequences from animal sources would be the most definitive way of revealing viral origins. For example, a future observation of an intermediate or fully formed polybasic cleavage site in a SARS-CoV-2-like virus from animals would lend even further support to the natural-selection hypotheses. It would also be helpful to obtain more genetic and functional data about SARS-CoV-2, including animal studies. The identification of a potential intermediate host of SARS-CoV-2, as well as sequencing of the virus from very early cases, would similarly be highly informative. Irrespective of the exact mechanisms by which SARS-CoV-2 originated via natural selection, the ongoing surveillance of pneumonia in humans and other animals is clearly of utmost importance.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

              A novel infectious disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in Wuhan, China, in December 2019. The disease (COVID-19) spread rapidly, reaching epidemic proportions in China, and has been found in 27 other countries. As of February 27, 2020, over 82,000 cases of COVID-19 were reported, with > 2800 deaths. No specific therapeutics are available, and current management includes travel restrictions, patient isolation, and supportive medical care. There are a number of pharmaceuticals already being tested [1, 2], but a better understanding of the underlying pathobiology is required. In this context, this article will briefly review the rationale for angiotensin-converting enzyme 2 (ACE2) receptor as a specific target. SARS-CoV-2 and severe acute respiratory syndrome coronavirus (SARS-CoV) use ACE2 receptor to facilitate viral entry into target cells SARS-CoV-2 has been sequenced [3]. A phylogenetic analysis [3, 4] found a bat origin for the SARS-CoV-2. There is a diversity of possible intermediate hosts for SARS-CoV-2, including pangolins, but not mice and rats [5]. There are many similarities of SARS-CoV-2 with the original SARS-CoV. Using computer modeling, Xu et al. [6] found that the spike proteins of SARS-CoV-2 and SARS-CoV have almost identical 3-D structures in the receptor-binding domain that maintains van der Waals forces. SARS-CoV spike protein has a strong binding affinity to human ACE2, based on biochemical interaction studies and crystal structure analysis [7]. SARS-CoV-2 and SARS-CoV spike proteins share 76.5% identity in amino acid sequences [6] and, importantly, the SARS-CoV-2 and SARS-CoV spike proteins have a high degree of homology [6, 7]. Wan et al. [4] reported that residue 394 (glutamine) in the SARS-CoV-2 receptor-binding domain (RBD), corresponding to residue 479 in SARS-CoV, can be recognized by the critical lysine 31 on the human ACE2 receptor [8]. Further analysis even suggested that SARS-CoV-2 recognizes human ACE2 more efficiently than SARS-CoV increasing the ability of SARS-CoV-2 to transmit from person to person [4]. Thus, the SARS-CoV-2 spike protein was predicted to also have a strong binding affinity to human ACE2. This similarity with SARS-CoV is critical because ACE2 is a functional SARS-CoV receptor in vitro [9] and in vivo [10]. It is required for host cell entry and subsequent viral replication. Overexpression of human ACE2 enhanced disease severity in a mouse model of SARS-CoV infection, demonstrating that viral entry into cells is a critical step [11]; injecting SARS-CoV spike into mice worsened lung injury. Critically, this injury was attenuated by blocking the renin-angiotensin pathway and depended on ACE2 expression [12]. Thus, for SARS-CoV pathogenesis, ACE2 is not only the entry receptor of the virus but also protects from lung injury. We therefore previously suggested that in contrast to most other coronaviruses, SARS-CoV became highly lethal because the virus deregulates a lung protective pathway [10, 12]. Zhou et al. [13] demonstrated that overexpressing ACE2 from different species in HeLa cells with human ACE2, pig ACE2, civet ACE2 (but not mouse ACE2) allowed SARS-CoV-2 infection and replication, thereby directly showing that SARS-CoV-2 uses ACE2 as a cellular entry receptor. They further demonstrated that SARS-CoV-2 does not use other coronavirus receptors such as aminopeptidase N and dipeptidyl peptidase 4 [13]. In summary, the SARS-CoV-2 spike protein directly binds with the host cell surface ACE2 receptor facilitating virus entry and replication. Enrichment distribution of ACE2 receptor in human alveolar epithelial cells (AEC) A key question is why the lung appears to be the most vulnerable target organ. One reason is that the vast surface area of the lung makes the lung highly susceptible to inhaled viruses, but there is also a biological factor. Using normal lung tissue from eight adult donors, Zhao et al. [14] demonstrated that 83% of ACE2-expressing cells were alveolar epithelial type II cells (AECII), suggesting that these cells can serve as a reservoir for viral invasion. In addition, gene ontology enrichment analysis showed that the ACE2-expressing AECII have high levels of multiple viral process-related genes, including regulatory genes for viral processes, viral life cycle, viral assembly, and viral genome replication [14], suggesting that the ACE2-expressing AECII facilitate coronaviral replication in the lung. Expression of the ACE2 receptor is also found in many extrapulmonary tissues including heart, kidney, endothelium, and intestine [15–19]. Importantly, ACE2 is highly expressed on the luminal surface of intestinal epithelial cells, functioning as a co-receptor for nutrient uptake, in particular for amino acid resorption from food [20]. We therefore predict that the intestine might also be a major entry site for SARS-CoV-2 and that the infection might have been initiated by eating food from the Wuhan market, the putative site of the outbreak. Whether SARS-CoV-2 can indeed infect the human gut epithelium has important implications for fecal–oral transmission and containment of viral spread. ACE2 tissue distribution in other organs could explain the multi-organ dysfunction observed in patients [21–23]. Of note, however, according to the Centers for Disease Control and Prevention [24], whether a person can get COVID-19 by touching surfaces or objects that have virus on them and then touching mucus membranes is yet to be confirmed. Potential approaches to address ACE2-mediated COVID-19 There are several potential therapeutic approaches (Fig. 1). Spike protein-based vaccine. Development of a spike1 subunit protein-based vaccine may rely on the fact that ACE2 is the SARS-CoV-2 receptor. Cell lines that facilitate viral replication in the presence of ACE2 may be most efficient in large-scale vaccine production. Inhibition of transmembrane protease serine 2 (TMPRSS2) activity. Hoffman et al. [25] recently demonstrated that initial spike protein priming by transmembrane protease serine 2 (TMPRSS2) is essential for entry and viral spread of SARS-CoV-2 through interaction with the ACE2 receptor [26, 27]. The serine protease inhibitor camostat mesylate, approved in Japan to treat unrelated diseases, has been shown to block TMPRSS2 activity [28, 29] and is thus an interesting candidate. Blocking ACE2 receptor. The interaction sites between ACE2 and SARS-CoV have been identified at the atomic level and from studies to date should also hold true for interactions between ACE2 and SARS-CoV-2. Thus, one could target this interaction site with antibodies or small molecules. Delivering excessive soluble form of ACE2. Kuba et al. [10] demonstrated in mice that SARS-CoV downregulates ACE2 protein (but not ACE) by binding its spike protein, contributing to severe lung injury. This suggests that excessive ACE2 may competitively bind with SARS-CoV-2 not only to neutralize the virus but also rescue cellular ACE2 activity which negatively regulates the renin-angiotensin system (RAS) to protect the lung from injury [12, 30]. Indeed, enhanced ACE activity and decreased ACE2 availability contribute to lung injury during acid- and ventilator-induced lung injury [12, 31, 32]. Thus, treatment with a soluble form of ACE2 itself may exert dual functions: (1) slow viral entry into cells and hence viral spread [7, 9] and (2) protect the lung from injury [10, 12, 31, 32]. Notably, a recombinant human ACE2 (rhACE2; APN01, GSK2586881) has been found to be safe, with no negative hemodynamic effects in healthy volunteers and in a small cohort of patients with ARDS [33–35]. The administration of APN01 rapidly decreased levels of its proteolytic target peptide angiotensin II, with a trend to lower plasma IL-6 concentrations. Our previous work on SARS-CoV pathogenesis makes ACE2 a rational and scientifically validated therapeutic target for the current COVID-19 pandemic. The availability of recombinant ACE2 was the impetus to assemble a multinational team of intensivists, scientists, and biotech to rapidly initiate a pilot trial of rhACE2 in patients with severe COVID-19 (Clinicaltrials.gov #NCT04287686). Fig. 1 Potential approaches to address ACE2-mediated COVID-19 following SARS-CoV-2 infection. The finding that SARS-CoV-2 and SARS-CoV use the ACE2 receptor for cell entry has important implications for understanding SARS-CoV-2 transmissibility and pathogenesis. SARS-CoV and likely SARS-CoV-2 lead to downregulation of the ACE2 receptor, but not ACE, through binding of the spike protein with ACE2. This leads to viral entry and replication, as well as severe lung injury. Potential therapeutic approaches include a SARS-CoV-2 spike protein-based vaccine; a transmembrane protease serine 2 (TMPRSS2) inhibitor to block the priming of the spike protein; blocking the surface ACE2 receptor by using anti-ACE2 antibody or peptides; and a soluble form of ACE2 which should slow viral entry into cells through competitively binding with SARS-CoV-2 and hence decrease viral spread as well as protecting the lung from injury through its unique enzymatic function. MasR—mitochondrial assembly receptor, AT1R—Ang II type 1 receptor
                Bookmark

                Author and article information

                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                28 October 2020
                November 2020
                : 13
                : 11
                Affiliations
                [1 ]Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA; Hsuhail1@ 123456hfhs.org (S.H.); irhaleb1@ 123456hfhs.org (I.A.R.)
                [2 ]Division of Cardiology, Department of Internal Medicine, University of Louisville Medical Center, Louisville, KY 40202, USA; kamkassem@ 123456gmail.com
                [3 ]Department of Physiology, Wayne State University, Detroit, MI 48201, USA
                Author notes
                [* ]Correspondence: nrhaleb1@ 123456hfhs.org ; Tel.: +1-313-432-7314
                Article
                pharmaceuticals-13-00347
                10.3390/ph13110347
                7692223
                33126450
                4a7a32ee-f2a8-4928-9952-81f70b073c06
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Review

                kallikrein–kinin system,bradykinin,b1 and b2 receptors,angiotensin-converting enzyme,angiotensin receptor blockers,hypertension,myocardial infarction,mice

                Comments

                Comment on this article