Evaluating the Implications of the Human Genome Project on ACE Inhibitors

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Evaluating the Implications of the Human Genome Project on ACE Inhibitors

Introduction

Perhaps the best epitome of global medical collaboration is the Human Genome Project. It started in 1990 and has been formally accomplished on April 14, 2003 – this is about 5 decades since the milestone marked by the discovery of the DNA helix by Watson & Crick [1].  Historically, the conceptualization of genome sequencing has been unofficially tackled among scientific circles since the onset of the 1980s. However, it has only been realized in 1988 following the documentation of the National Research Council of a research roadmap for genome sequencing and the template organisms that may be utilized for the project [2]. The report of the council has projected that the Human Genome Project would span 15 years and would entail about $2.7 billion in investment. The project has been earmarked as global, collaborative undertaking. In fact, there have been 20 satellite sequencing offices situated in 6 countries. It is worth noting that 5 such centers in the US and the UK have been most instrumental in pushing forth the project. Moreover, they have allotted about 5% of their cost to addressing “ethical, legal, and social implications” of the scientific investigations being undertaken. Since then, there have been noteworthy commentaries and approaches that have been put forth regarding the Human Genome Project [3-4].

One of the more contemporary and critical facets of the project has been the discovery of ACE-2 inhibitors that may potentially be a more effective palliative for cardiovascular disease. Given this brief background on the Human Genome Project and its prospects for novel drug discovery, it is worth delving further on a review of related literature suggesting the progress made on ACE2. The potential of ACE2 as illustrated by Human Genome experiments shall be presented in the succeeding sections, following the statement of the problem and methodology.

Statement of the Problem

The present study aims to answer the following research question: What is the current status of studies dedicated to the discovery of new ACE 2 inhibitors? Once a review of these empirical investigations has been accomplished, the prospects of these on the cure of cardiovascular diseases may also be assessed.

Methodology

The study is limited to an investigation of secondary data to undertake an extensive review of the available literature on ACE 2 inhibitors and the projects that have been dedicated specifically for them. All empirical investigations from 1990 to the present shall compose the literature review. Once gathered, these studies shall be presented and critically analyzed by theme. An assessment of the implications and prospects of ACE 2 inhibitors shall be made following the critique.

Critique of Literature

The Status of the Human Genome Project

The Human Genome Project has been launched in the 1990s, and since then has made milestones in three core areas, namely, 1) drafting genetic maps; 2) determining physical maps; and sequencing [5]. All the genetic maps have been identified, encompassing the fullness of the human genome. The same trend is true in determining physical maps, where there has been 97% completion, making possible the identification of genes accountable for certain diseases. Efforts towards sequencing are also being reinforced, and to date, 6% of the sequence has already been laid down, and a separate 12% is about to be completed. Utilizing random sequencing methods, identification and mapping of genes is being undertaken. Overall, there are about 40 thousand out of 100 thousand genes identified, and 30 thousand have already been mapped [5].

What is the status of the Human Genome Project now? It has marked completion in April 14, 2003, about five decades since Watson and Crick’s discovery of the DNA helix [1]. The National Research Council Report of 1998 has been instrumental in making the Human Genome Project a reality, with its recommendation for a dedicated project specially aimed at mapping and sequencing of the human genome. This was carried out using model organisms [6]. Originally, it has been projected that the project shall be completed after 15 years; it has been finished relatively earlier at 12.5 years, and with a total expense of $2.7 billion dollars [3].

Clinical Benefits of the Human Genome Project

Human genome sequencing in itself may be considered as a scientific milestone; however, in itself, it does not have any immediate scientific advantage. Both extreme perspectives on the utility of the project have surfaced; on one end, there are those who see the project as a panacea for disease, while the other extreme cynically dismisses any or little benefit into medicine [7].

Collins et al [3] relates that there are conferences sponsored by the National Human Genome Research Institute in 2001 and 2002 which has laid down the vision for genomics research. This vision anticipates the main areas in which the Human Genome Project would exert significant impact. These are basic biology, health and society. This vision is vividly represented in Figure 1 below. The components that are envisioned to lend support across these areas are depicted as pillars, and these include “education and training, technology development, and consideration of ethical, legal and social implications” of the project [3].

The second floor of this structure depicts Genomics to Health which encompasses the following goals: “1) to identify genes and pathways involved in disease; 2) to develop and apply genome-based methods for disease diagnosis, disease classification, and prospective prediction of disease susceptibility and drug response; and 3) to catalyze new development of new therapeutics based on genomic information” [3].

Figure 1 Impact of the Human Genome Project [3].

Before discussing the prospects of ACE2 as a hypertensive treatment for hypertension, it may be worthwhile to discuss hypertension as a medical condition. This is done so in the following section.

Hypertension

Hypertension is a popular condition which is characterized by the constriction of arteries. A logical outcome is the increased pressure that has to be exerted for blood to be pumped, causing cardiovascular and arterial wall tension. If not addressed promptly, this may lead to complications not only in the heart but in other key organs including the brain, kidneys and the brain [8]. Moreover, those who are afflicted with the disease have a higher probability of suffering from a stroke. It merits research attention, considering the complexity of its determinants. It is projected that a fourth of adults are suffering from the disease and the likelihood of suffering from it goes up as the individual matures. Finally, the condition cannot be cured but may be effectively controlled through medication [8].

Many doctors and scholars in the field of medicine have intimated that high blood pressure is oftentimes an indicator and a primary cause of heart disease. That is, hypertension is considered by many as a multi-factorial quantitative trait, which is controlled by genetic and environmental factors. These environmental factors include diet and physical activity. However, not much is known about the genetic attributes that may entail the possibility of succumbing to hypertension or other cardiovascular diseases. Though there have been quite a number of studies conducted to determine several putative genetic quantitative trait loci (QTL) associated with hypertension in animal models, these are not enough. There is still a need to have these loci to be translated into genes. For that reason, studies that would ascertain the molecular and genetic mechanisms that set off hypertension and other cardiovascular diseases are lacking [9].

ACE2 and Hypertension

ACE-2 or angiotensin converting enzyme is a contemporary human homolog of ACE. It is a new metallocarboxypeptidase whose chemical and functional properties are dissimilar from those of ACE. This substance is predominantly located in the vascular endothelial cells of the kidney and heart. The new enzyme is said to play a critical part in renin-angiotensin mechanisms and in heart and kidney systems as well [10]. It is from the human heart that ACE2 has been first cloned. In contrast with ACE, it only has one enzymatic site that acts as a catalyst for the attachment of angiotensin I to angiotensin 1-9. Moreover, it is not inhibited by customary ACE inhibitors and is capable of altering angiotensin II to angiotensin 1-7 [11]. The exact mechanisms of ACE2 regulation in renin-angiotensin processes have not been researched; however, these processes and the system itself is a suspected root cause of complications in diabetes.

Properties and Functions of ACE2

Of late, there has been the momentous discovery of an additional type of ACE which is popularly tagged as ACE2. In essence, it is a critical controller of cardiovascular processes [9]. It is said to be distinct from ACE since it has only one zinc-binding catalytic site. Moreover, it is a carboxypeptidase which is inclined towards carboxy-terminal hydrophobic or basic residues. Finally, it is not influenced by ACE inhibitors. Angiotensin I and II, as well as several peptides known to be biologically active, are substrates for ACE2, but bradykinin is not. When scrutinized, the genomic structures of ACE and ACE2 were brought forth from the same lineage. X-ray structures of a “truncated, deglycosylated form of germinal ACE and a related enzyme” hailing from Drosophila have been documented, and these show that the active site is deep within a core, central cavity. The structure-based drug designs of the specific active sites of somatic ACE may bring forth a novel league of ACE inhibitors that pose the promise of fewer side effects than those offered by presently available inhibitors [9].

ACE2 has a variety of functions. Thus, being basically a carboxy-peptidase substance, it allows the cleaving of a single residue from AngI for the generation of Angl-9 [12-13] and the cleaving of a single residue from AngII for the production of Angl-7 [13]. It was also said that ACE2 can cleave other peptide substrates. Considering these functions in the in vitro biochemical data, ACE2 appears to be capable of modulating the renal angiotensin system (which has a critical function in controlling the mechanisms of hypertension) and thus able to affect blood pressure regulation. But then again, the in vivo role of ACE2 in the cardiovascular system and the RAS is still unidentified.

Hypertension and Its Treatments

Hypertension is a popular condition which is characterized by the constriction of arteries. A logical outcome is the increased pressure that has to be exerted for blood to be pumped, causing cardiovascular and arterial wall tension. If not addressed promptly, this may lead to complications not only in the heart but in other key organs including the brain, kidneys and the brain [14]. Moreover, those who are afflicted with the disease have a higher probability of suffering from a stroke. It merits research attention, considering the complexity of its determinants. It is projected that a fourth of adults are suffering from the disease and the likelihood of suffering from it goes up as the individual matures. Finally, the condition cannot be cured but may be effectively controlled through medication [8].

The National High Blood Education Program has released the complete report about hypertension to inform and guide patients on how to manage and prevent the condition.  It has been emphasized that 50-year old individuals with high systolic blood pressure are likely to develop a cardiovascular disease and 55-year old normotensive individuals have greater risks of having hypertension [15]. Individuals who are said to be prehypertensive must have a healthier lifestyle to prevent hypertension and CVD.  Drugs like thiazide can be used to treat hypertension but if the patient is diabetic or suffering from a chronic kidney disease, thiazide and antihypertensive drugs with angiotensin must be given. Patients must cooperate in their treatment plan that will help in controlling hypertension. In particular, the US only has a minor percentage of 34% of individuals suffering from the condition who undertake BP control to the suggested 140/90 level through drug interventions [15]. Obviously, this results in deaths which could have been prevented if they had undergone BP control. Given the dire consequences of ineffective hypertension management, it is critical to find the most effective and viable cure for the condition.

Among the cures available for hypertensive treatment, there have been conflicting findings as to the utility of ACE inhibitors. These are seen among various patient groups. One meta-analysis conducted has demonstrated that ACE inhibitors and betablockers accord very positive gains for females, blacks and individuals inflicted with diabetics and heart failure. This gives significant assurance for physicians that ACE inhibitors may be utilized to diverse patient populations [16]. However, there are certain exceptions, including females with asymptomatic left ventricular (LV) systolic dysfunction, who present no life-saving benefits when administered the inhibitors. Shekelle et al  [17] of the Greater Los Angeles VA Medical Center, CA) assert in their study published in the Journal of the American College of Cardiology that majority of blacks, with the exception of bucindololas, did not manifest such positive response as attested to by the BEST experiments [17]. These constraints on currently available treatments for hypertension have spurred further research on more effective cures. This thrust has been given new hope with the discovery of ACE2 through the Human Genome Project.

It is thus noteworthy to track the studies which indicate the potential of ACE2 as a treatment for hypertension, through a review of the genetic studies that demonstrate such treatment potential. These studies are presented below:

Genetic Studies Demonstrating the Potential of ACE2 as a Treatment for Hypertension

The Discovery of ACE2. Donoghue [12] is one of the two independent groups that have led to the discovery of ACE2. Numerous studies have shown how reactive oxygen species (ROS) cause the malfunction of endothelium-dependent vascular responses. The vascular NAD(P)H oxidases have also been therapeutic targets for cardiovascular diseases. According to the study made by Griendling et al [12] the activation of these said oxidases as well as the production of reactive oxygen species by enzyme systems are common in a cardiovascular disease. A non-phagocytic NAD(P)H oxidase proteins have been discovered to play a role in vascular tissues.

The human heart has enzymes that when split up produces Ang I, and releases products that may possibly counteract the actions of Ang II. This process leads to inflammation, hypertrophy, remodeling, and angiogenesis. Donoghue et al [12] experimented on mice that are deficient in p47 (phox) and gp91 (phox/NOX2). Results showed that the ROS produced by the oxidases contribute to the cardiovascular diseases including atherosclerosis and hypertension. Therefore an endothelial source containing this oxidase should be considered when evaluating the effect of this enzyme on endothelium-dependent relaxation and vascular homeostasis [12].

Link of ACE2 to QTL. Heart diseases are projected to be the most usual death cause globally by the year 2020. Acknowledging this, Crackower et al [18] have carried out a study to illustrate that angiotensin-converting enzyme 2 (ACE2) matches to a specific quantitative trait locus (QTL) on the X chromosome in 3 various types of mouse models of hypertension [53]. ACE2 messenger RNA and the expression of protein were distinctly decreased in all types, indicating that the gene is suited to such QTL. The customized disturbance of ACE2 in rats causes a chronic contractibility effect, heightened amounts of angiotensin II, and increased degrees of hypoxia-related coronary genes. Genetic ablation of ACE on an ACE2 mutant background completely rescues the cardiac phenotype. There is a chronic defect of heart morphogenesis rooted in the disruption of ACER, a Drosophila ACE2 homologue. This study lends proof to the promise of ACE2 as a critical component in the in vivo regulation of cardiac function [18].

ACE2 and Myocardial Ischemia. Another study linking that was done as an outcome of ACE2 human genome research is that conducted by Burrell et al [19]. The researchers carried out a study which  focused on the catalyzing capacity of ACE2 in the cleavage of AngI to Ang1-9 and of AngII to Ang1-7. It has been noted that a lack in ACE2 decreases the ability of the heart to contract and “upregulates hypoxia-induced genes.” These findings suggest that ACE2 inhibitors are related to myocardial ischaemia.

ACE2 and RAS Regulation following Cardiac Dysfunction. Burrell et al [19] went on to investigate the manifestation of ACE2 following myocardial infarction in mice as well as in dysfunctional human hearts. The methodology involved killing mice subjects at 1, 3 and 28 days following the experience of MI or receiving 4-week treatment with ramipril, which is an ACE inhibitor (1 mg/kg). An evaluation of the cardiac gene and protein manifestation of both ACE and ACE2 followed and it has been observed that both ACE and ACE2 mRNA presence rose in the border area vis-à-vis the viable area at day 3 consequent to MI. A similar trend of increase has been observed for day 28. Moreover, ACE2 protein has been concentrated to “macrophages, vascular endothelium, smooth muscle, and myocytes.” Ramipril has also been found to derail cardiac ACE, but has no impact on heart ACE2 mRNA which did not change in concentration in the hearts of mice subjects. There has also been a rise in immunoreactivity in both ACE and ACE2 in dysfunctional human hearts. This rise in ACE2 following MI indicate that it has a crucial role in the regulation of the renin angiotensin system in the generation and degradation of angiotensin peptides following cardiac dysfunction or damage [19].

More Into the Capacities of ACE2. Tikellis et al [11] attempted to evaluate the role of ACE2 in the renal functions of diabetic mice and provide a benchmark against which ACE functioning may be compared. The gene and protein expression of both enzymes in the kidney have been assessed following 24 weeks of streptozocin diabetes. It has been noted that ACE2 and ACE mRNA amounts went down by half (or 50%) in diabetic tubules of the kidney and were not affected by ramipril – which is an ACE inhibitor. They also subjected both enzyme types to immunostaining and this caused them to be mainly localized into the kidney tubules. There was also a marked decline in the expression of ACE2 protein in the diabetic kidney, assumed to be precluded by ACE inhibitor intervention. These discoveries suggest that ACE2 is capable of moderating diabetes apart from its cardiovascular mediating capacity [11].

The Discovery of More Peptide Inhibitors. Huang et al [10] undertook a study towards the revelation of novel ACE2 peptide inhibitors done through the choice of limited peptide sets exhibited on phage. In this research, there were six “constrained peptide libraries” that were built and chosen over FLAG-tagged ACE target. In addition, ACE2 peptide binders were determined and categorized into five clusters, in accordance with their impact on ACE activity [10]. Newly discovered ACE2 specific peptide inhibitors from this and similar projects are expected to shed more light into ACE2 in vivo mechanisms and ultimately to a more effective comprehension of its relationship to cardiovascular function. Outcomes from this research illustrate that library selection through phage display technology can be used as an effective means of further revealing novel, powerful and specific protease inhibitors, consistent with what has been done in the human genome project [10].

ACE2 as a New Target for Hypertension Gene Therapy. Katovich et al [20] undertook a study on the Angiotensin-Converting Enzyme 2 (ACE2) as a new potential target of gene therapy for hypertensive disorders. According to statistics, less than one-third of patients suffering from hypertension have their blood pressures (BP) controlled with current yet traditional therapeutic approaches for the treatment and control of the disease. Though many of these pharmacological approaches reached a certain level of effectiveness, they do not necessarily provide the cure for hypertension. Therefore, experts need to study newer and more innovative strategies to not only increase the number of patients who can achieve BP control and manage hypertension, but rather find a way to cure it [20]. This protein was originally found in the testis, kidney, and heart but has now been identified in a wide variety of tissues. ACE2 is just one of the several enzymes that regulate cardiac contractility and Angiotensin 1 and 2 levels. The Renin-Angiotensin System (RAS) plays a critical role in blood pressure regulation and fluid hemodynamics. Pharmacologic strategies of RAS are routinely used to treat hypertension [20]. The two research groups used mice as their analytical models. These mice have normal renal development and glomerular function so they serve as useful models for this study.

The data results gathered suggested that the animals are anemic and the anemia associated with the interruption of the RAS was due to the lack of Ang 2 production. This supported the concept that Ang 2 does facilitate erythropoiesis, the development of mature red blood cells. The fact that ACE2 has potential tissue effects signifies that it has implications on the clinical management or as a therapeutic target for hypertension. Various research entities now plan to develop specific promoters and appropriate regulatory gene switches to regulate the expression of the transgenic ACE2. Thus ACE2 is a potentially important treatment opportunity for hypertension and related heart diseases [20].

There has also been evidence suggesting that the overexpression of ACE2 did not cause cardiac hypertrophy nor fibrosis when the hypertensive agent was chronic angiotensin II treatment. And yet the overexpression did not preclude the rise of blood pressure [21]. The presence of ACE2 which is both secreted and membrane-bound may led to the delivery of the gene independent of RAS. Thus, this may lead us to “differentiate the effects of tissue and systemic over-expression of ACE2 on both BP control and related cardiovascular disease management” [21] Katovich et al [21] intends to do research on particular promoters and apt gene switches for transgenic ACE2 expression. Such overexpression may embody a chance for more effective hypertension treatment. They also assert that “a cell-selective, regulatable lenti vector system utilizing such a promising novel target transgene could bring gene therapy for hypertension one step closer to application in man” [21]

Conclusion

It is just very recently that ACE2 has been a recently discovered enzyme which is present in both mice and humans. The criticality of the enzyme in both healthy and dysfunctional physiological states has yet to be fully researched. ACE2 has a more constrained distribution compared to ACE, with renal and cardiac manifestations. Knockout researches that have focused on ACE2 have shown the prospective role of ACE 2 in heart function. There may be a need to further investigate the effects of ACE2 in the production of angiotensin and kinin peptides and heart disorders [22]. Through the human genome project, there have been numerous milestones attained for the prospective use of ACE2 in the treatment of hypertension and similar cardiovascular diseases. It is projected that ACE2 will be the main focus for the growth of medical research pertinent to the treatment of heart disease.

The role of doctors for furthering ACE2 research is indeed critical. Dr. Collins, the present director of the National Human Genome Research Institute, reinforced that physicians ought to spearhead the discovery of practical uses of genomics among patients inflicted with various diseases. He cites that the Human Genome Project started in 1990 with the serious intent of mapping the human genetic code. The herculean task involved  studying 3 billion base pairs which compose the human genome and nearly 25,000 genes that are responsible for the mechanisms transpiring within the human body. In fact, the project has been tagged as “the most significant scientific milestone of all time” [23]. The milestones cited in the current review attest to the promise of the human genome project in discovering more effective medication for hypertensive patients.

The completion of the Human Genome Project has indeed been a scientific milestone; however, it ought to come alongside active drug development and physician competencies that will allow the them to leverage on novel genome-based interventions and therapeutic means. Enhanced comprehension on disease biology and the categorization of “phenotypically defined diseases” into molecular representations have already been initiated [24]. It is projected that in the near future, diagnostic tools and treatments for common diseases such as hypertension and the rise of gene-sequence based tests for the determination of drug dosages to specific patient types are impending. The increased collaboration between private and public entities to strengthen the drive towards drug development – including those involving ACE2 research – is projected. Overall, these efforts shall lead to the realization of the promise of the Human Genome Project [25].

References

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[8]  Available from http://genome.wellcome.ac.uk/doc_WTD020942.html

[9]  Riordan J 2003. Angiotensin converting enzymes and its relatives. Available from http://genomebiology.com/2003/4/8/225

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[11] Tikellis C, Johnston CI, Forbes JM et al. 2003 Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy. Hypertension 41:392–397.

[12] Donoghue M, Hsieh F, Baronas E et al. 2000. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 87:E1–E9.

[13]  Tipnis SR, Hooper NM, Hyde R et al. 2000. A human homolog of angiotensin-converting enzyme—cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem  275:33238–33243.

[14] Lewis et al 1993

[15] Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jones DW, Materson BJ, Oparil S, Wright JT, Roccella EJ & the National High Blood Pressure Educational Program Coordinating Committee. (2003). Seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Hypertension 42, 1206–1252.

[16]  Nainggolan L 2003 ACE inhibitors and beta blockers benefit most people with HF. Available from  http://www.theheart.org/viewArticle.do?simpleName=322185

[17]   Shekelle P et al 2003 Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status. A meta-analysis of major clinical trials. May 7 41(9):1529-38

[18] Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, da Costa J, Zhang L, Pei Y, et al. 2002. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417: 822-828.

[19]  Burrell, L., Risvanis, J., Kubota, E., Dean, R., MacDonald, P., Lu, S. et al (2005). Myocardial infarction increases ACE2 expression in rat and humans. European Heart Journal 26(4), 322-324.

[20] Iyer SN, Ferrario CM & Chappell MC (1998). Angiotensin-(1–7) contributes to the antihypertensive effects of blockade of the renin-angiotensin system. Hypertension 31, 356–361.

[21] Katovich M, Grobe J, Huentelman M & Raizada M. Angiotensin-converting enzyme 2 as a novel target for gene therapy for hypertension.

[22]  Oudit GY, Crackower MA, Backx PH et al. 2003 The role of ACE2 in cardiovascular physiology. Trends Cardiovasc Med 13:93–101

[23]  Collins FS. 2004. Genomics and the family physician: realizing the potential. Program and abstracts of the American Academy of Family Physicians 2004 Annual Scientific Assembly October 13-17, 2004 Orlando, Florida. Session 003.

[24] Alizadeh AA, Ross DT, Perou CM, van de Rijin M. 2001. Towards a novel classification of human malignancies based on gene expression patterns. Journal of Pathology 195: 41-52.

[25] Guttmacher AE & Collins FS. 2003. Welcome to the genomic era. N Engl J Med 349: 994-996.

 

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