ACE2

Angiotensin-converting enzyme 2 (ACE2) is a critical component of the renin-angiotensin system that plays a distinct role from its homolog ACE in cardiovascular physiology and pathology. 

Identified in 2000, ACE2 uniquely counters the effects of ACE by converting angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), a peptide that dilates blood vessels and offers cardioprotective benefits. 

Unlike ACE, ACE2 does not degrade bradykinin and also converts angiotensin I (Ang I) into Ang(1–9), further moderating cardiovascular functions.

While ACE contributes to vasoconstriction and hypertension by increasing Ang II levels, ACE2 enhances cardiovascular protection by reducing these levels and mitigating their harmful effects. 

In addition to its balancing act with ACE, ACE2 also plays a role in the pathogenesis of certain viral diseases, including COVID-19.  ACE2 serves as a receptor for the COVID-19 virus, facilitating its entry into cells.

Clinically, the modulation of ACE2 activity presents potential therapeutic avenues, particularly in conditions exacerbated by high Ang II levels, such as certain cardiovascular and renal diseases. 

Genetic variations in the ACE2 gene, including single nucleotide polymorphisms (SNPs), offer insights into individual susceptibilities and responses to various health conditions, underlining the importance of ACE2 in both health and disease.

What is ACE2?  [10.]

Angiotensin-converting enzyme (ACE) and its homolog angiotensin-converting enzyme 2 (ACE2) are pivotal in the renin-angiotensin system, impacting cardiovascular physiology and pathology differently.  

ACE, discovered in the mid-1950s, primarily converts angiotensin I (Ang I) to the vasoconstrictor angiotensin II (Ang II), and degrades the vasodilator bradykinin, enhancing blood pressure regulation.  This role led to the development of ACE inhibitors in the 1970s, like captopril, aimed at treating hypertension by reducing Ang II levels and increasing bradykinin.

Discovered in 2000, ACE2 differs fundamentally by converting Ang II into Ang(1–7), a peptide that opposes Ang II's effects by dilating blood vessels and exerting cardioprotective actions through the Mas receptor signaling pathway. 

Unlike ACE, ACE2 does not degrade bradykinin. It also transforms Ang I into Ang(1–9), which ACE can further convert to Ang(1–7).  This conversion chain underlines ACE2’s crucial role in balancing the effects of Ang II, tilting towards cardiovascular protection.

Structurally, ACE comprises two catalytic domains and is linked to the membrane via a stalk that can be cleaved, influencing its plasma activity. In contrast, ACE2 features a single catalytic domain and a collectrin-like domain, suggesting different regulatory and functional interactions.

Clinically, ACE inhibitors have been foundational in managing hypertension and heart failure by mitigating ACE's blood pressure-raising actions.  Conversely, the modulation of ACE2 activity or expression offers potential therapeutic avenues, especially in conditions exacerbated by elevated Ang II levels, like certain cardiovascular and kidney diseases.

ACE2 also serves as a receptor for several human coronaviruses, including SARS-CoV and SARS-CoV-2, the latter being responsible for COVID-19.  The enzyme's interaction with the spike glycoprotein of these viruses facilitates their entry into cells, highlighting its pivotal role in viral pathogenesis. 

Genetically, the ACE gene is located on chromosome 17 and includes variants that significantly influence ACE activity and related cardiovascular risks.  ACE2 is positioned on the X chromosome.

Various splice variants of ACE2 have been identified, including an interferon-inducible variant, dACE2 (or MIRb-ACE2), which further suggests its involvement in immune responses.

In summary, while both ACE and ACE2 play critical roles in blood pressure regulation and cardiovascular health, their functions balance each other.

ACE2 in Kidney Health  [6.]

ACE2 also balances the effects of ACE in the kidneys, aiding in preserving renal function.  

ACE2 balances the effects of the classical ACE-Angiotensin II-Angiotensin 1 receptor axis through its unique ability to convert angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), a vasodilator that mitigates vasoconstriction, water retention, and salt intake. 

This conversion effectively reduces the levels of Ang II, decreasing its pro-fibrotic and inflammatory effects on renal tissues. 

Predominantly expressed in the proximal tubules and, to a lesser extent, in the glomeruli of the kidneys, ACE2 plays a protective role in renal health.  By promoting the production of Ang 1-7, ACE2 not only counters the harmful effects of Ang II but also supports renal protective pathways via the Mas receptor. 

The non-classical ACE2-Ang 1-7-Mas axis serves as a counter-regulatory mechanism to the classical RAS pathway, highlighting its potential as a therapeutic target in renal diseases characterized by dysregulated Ang II activity.

Genetic Alterations in the ACE2 Gene

The gene for the ACE2 protein may contain alterations or mutations that cause alterations of function of the ACE2 protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Specific SNPs Associated with Alterations in Function of ACE2  [1.] 

As a critical receptor for SARS-CoV-2, ACE2 has a significant role in the pathogenesis and outcomes of COVID-19 infections. 

The G8790A (rs2285666) and A2350G (rs4343) polymorphisms have been studied for their effects on an individual’s susceptibility and severity of COVID-19. 

Individuals with the GG genotype of both A2350G and G8790A exhibit a higher susceptibility to COVID-19, although these genetic variants do not appear to influence the severity of the disease.  

This suggests that these specific ACE2 gene polymorphisms might affect the expression and functionality of ACE2, potentially altering the individual's response to SARS-CoV-2 infection. 

Further research with a larger cohort is necessary to confirm these associations and fully understand the implications of ACE2 polymorphisms in COVID-19 susceptibility and pathogenesis.

Laboratory Testing for ACE2

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home. 

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing.  

Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles. 

Related Biomarkers to Test

ACE (Angiotensin Converting Enzyme I)  [2., 4., 5., 6., 7.] 

Angiotensin-converting enzyme (ACE) is an essential component of the renin-angiotensin system, a critical regulator of blood pressure and fluid balance within the body.  While ACE2 tends to reduce blood pressure, ACE catalyzes the transformation of angiotensin I into angiotensin II, with the overall goal of increasing blood pressure. 

This potent vasoconstrictor not only elevates blood pressure but also prompts the adrenal cortex to secrete aldosterone, further influencing blood pressure and fluid balance.  Moreover, ACE deactivates the vasodilator peptide bradykinin, further increasing blood pressure.

ACE’s activity is particularly significant in cardiovascular and renal functions.  Angiotensin II, produced by ACE, contributes to cardiovascular challenges like cardiac remodeling, vascular inflammation, and endothelial dysfunction, which play roles in hypertension, atherosclerosis, and heart failure. 

In the kidneys, ACE is crucial for regulating both the glomerular filtration rate and renal blood flow.

Laboratory testing for ACE levels provides insights into its activity and implications in clinical settings, helping monitor conditions like sarcoidosis and assess genetic variations linked to diverse diseases, including cardiovascular and renal disorders.  

Renin  [3., 9.] 

Renin, an enzyme produced by the juxtaglomerular cells of the kidney, initiates the RAAS cascade by catalyzing the conversion of angiotensinogen to angiotensin I. 

As the primary regulator of RAAS activity, renin plays a central role in blood pressure regulation and fluid balance.  Measurement of plasma renin activity (PRA) or renin concentration provides valuable information about RAAS activation and may aid in the diagnosis and management of hypertension, heart failure, and renal disorders. 

Elevated renin levels are often observed in conditions characterized by hypovolemia, while decreased renin levels may indicate RAAS suppression or volume expansion.

Aldosterone  [8.] 

Aldosterone, a mineralocorticoid hormone secreted by the adrenal cortex, acts on the distal nephron to promote sodium retention and potassium excretion, thereby regulating electrolyte balance and blood pressure.  Aldosterone synthesis and release are tightly regulated by RAAS components, including angiotensin II and ACE. 

Measurement of plasma aldosterone concentration (PAC) or aldosterone-to-renin ratio (ARR) can provide insights into aldosterone production and RAAS activity. 

Elevated aldosterone levels are associated with conditions such as primary aldosteronism, hypertension, and heart failure, while decreased aldosterone levels may occur in conditions such as adrenal insufficiency or hypoaldosteronism.

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