In 2003, a novel enzyme burst onto the scene of medical science, known as angiotensin-converting enzyme 2 (ACE2). Scientists quickly recognized its significance in regulating blood pressure and cardiovascular function, drawing attention from medical communities worldwide. Fast forward to recent years, and ACE2 has found itself as the key entry point for the SARS-CoV-2 virus responsible for the COVID-19 pandemic. But ACE2’s story is far richer than its association with this modern-day plague.
Recent research published in Nature Communications explores ACE2’s multifaceted role in cardiovascular and pulmonary health. It taps into a world where engineered mouse models help scientists unravel the mysteries of this enzyme, revealing crucial insights into how it operates and opens avenues for potential therapeutic advancements. This article dives into the heart of that research, explaining the profound implications for understanding diseases and developing treatments.
Before delving into the experimental intricacies, it’s worth revisiting ACE2’s basic function. ACE2 serves as a regulatory enzyme within the renin-angiotensin system (RAS), a hormone system that manages blood pressure, fluid, and electrolyte balance. Think of RAS as a sophisticated plumbing network of hormones and receptors. ACE2 acts as the cataclysmic release valve, transforming the potent vasoconstrictor Angiotensin II (Ang II) into Angiotensin-(1–7) (Ang-(1–7)), a molecule that counters Ang II’s tightening grip on blood vessels.
By mitigating Ang II’s effects, ACE2 grants our arterial highways a certain degree of relaxation, reducing pressure and protecting against damage. However, ACE2 is not restricted to merely regulating pressure; it plays multiple roles in various tissues, offering protective effects to the heart, lungs, kidneys, and even the pancreas. Hence, any alteration in ACE2 function, as seen during COVID-19 infection, can ignite a cascade of systemic effects.
The research at the heart of this article focuses on dissecting these roles using specialized murine (mouse) models genetically engineered to either lack ACE2 or express human versions of the enzyme. Jiang, Yue, and Lazartigues led the charge in this comprehensive study, generating valuable tools to probe ACE2’s biological mechanisms and disease implications. The creation of these models involved sophisticated genetic tinkering, akin to replacing parts in a high-precision car engine to observe the resulting changes in performance.
One standout model involves the selective deletion of ACE2 from neurons, shedding light on its role within the brain. Using synapsin1-cre mice (a strain engineered to facilitate neuron-specific genetic modifications), researchers demonstrated significant reductions in ACE2 activity in the brain, impairing neuronal inhibition. Picture a meticulously orchestrated symphony where suddenly one instrument falls out of tune—such is the effect on neuronal function when ACE2 is absent.
This reduced neuronal inhibition had cascading effects on blood pressure regulation, implicating a critical ACE2 role in managing autonomic functions and cardiac health. Further investigations pinpointed ACE2 presence on the inhibitory neurons themselves, hinting at its direct involvement in maintaining the balance between excitatory and inhibitory signals in the brain.
Another striking model featured ACE2 knockout mice in lung epithelial cells, developed by crossbreeding floxed mice with Foxj1cre mice. Researchers subjected these mice to bacterial pneumonia induced by Pseudomonas aeruginosa, observing a dramatic increase in weight loss, lung injury, and inflammation compared to their wild-type counterparts. Such findings underscored ACE2’s critical function in modulating respiratory inflammation, a vital clue for understanding COVID-19’s ravaging effects on the lungs.
Beyond the physiological observations, the study detailed the underlying biochemical interactions leading to these results. During inflammatory responses, ACE2 modulates the immune cell infiltration and cytokine release within the lung tissue. Without ACE2, these processes ran amok, highlighting its role in maintaining immunological harmony amid pathogenic assaults.
Equally riveting are the findings from adipocyte-specific ACE2 knockout models, which elucidated ACE2’s role in metabolic and cardiovascular regulation. Shoemaker et al. engineered these mice to lack ACE2 in fat cells, revealing increased systolic blood pressure and heightened acute responses to Ang II. The outcomes paint a clear picture of ACE2’s importance in adipose tissues, especially regarding sex differences in obesity-related hypertension. Estrogens upregulate ACE2 expression in female adipose tissue, offering a degree of protection against Ang II’s hypertensive effects. In the absence of ACE2, this protective buffer crumbles, resulting in elevated blood pressure.
The study’s findings extend beyond metabolic implications, hinting at broader cardiovascular risks in conditions where ACE2 function is impaired, such as during SARS-CoV-2 infection. The interplay between ACE2 and Ang II takes center stage in understanding these risks. As Ang II levels surge unchecked, their interaction with receptors like AT1R (Angiotensin II type 1 receptor) triggers vasoconstriction, oxidative stress, and inflammatory pathways—all contributing to cardiovascular harm.
Digging further into the molecular dance, the researchers uncovered the ACE2-ADAM17 interaction’s intricacies. ADAM17 is a sheddase enzyme that cleaves ACE2 from cell surfaces, thus regulating its availability. This meticulous regulation ensures a balanced response to physiological needs and stresses. However, during heightened Ang II activity, ADAM17’s role becomes prominent, leading to increased ACE2 shedding and subsequent reductions in its protective effects.
But what about ACE2’s link to SARS-CoV-2? As the infamous gateway for this virus, ACE2’s expression levels and activity prove critical in understanding COVID-19’s progression and severity. By creating mouse models expressing human ACE2 (hACE2), researchers like McCray et al. demonstrated heightened susceptibility to SARS-CoV-2 infection, offering a proxy to study the disease’s pathogenesis. These models revealed extensive viral replication in lungs and other tissues, aligning closely with human clinical observations.
However, any study must acknowledge its limitations. Animal models, while invaluable, cannot perfectly replicate human physiology. Variance in gene expression, immune responses, and disease courses between species mark inherent constraints in translating findings directly to human contexts. Moreover, while the knockout and transgenic models elucidate ACE2’s functions, they cannot capture the full spectrum of genetic and environmental interactions influencing real-world outcomes.
Nevertheless, the implications for therapy and prevention are profound. Understanding ACE2’s multi-faceted roles paves the way for novel therapeutic targets, particularly in cardiovascular and pulmonary diseases. For instance, enhancing ACE2 activity or preventing its downregulation could mitigate Ang II’s harmful effects, providing cardiovascular protection. Alternatively, therapeutics aiming to modulate ADAM17’s sheddase activity offer another promising avenue, potentially preserving ACE2’s availability where it’s needed most.
Furthermore, ACE2’s interaction with SARS-CoV-2 invites intriguing prospects for antiviral strategies. Blocking ACE2-spike protein binding could thwart viral entry, limiting infection spread. Moreover, therapies bolstering ACE2 levels in the lung might reduce the severe inflammatory responses characterizing COVID-19, providing relief to those struggling with severe illness.
The road ahead teems with potential research directions. Larger, more diverse studies across different genetic backgrounds can validate findings and uncover nuanced effects. Moreover, exploring ACE2’s role in other diseases such as diabetes, kidney injury, and neurodegenerative conditions could broaden our therapeutic arsenal, tapping into this enzyme’s vast potential.
In the words of the authors: “Over the past two decades, numerous genetically engineered mouse models have been generated to understand the role of ACE2 with regards to cardiovascular, pulmonary, and infectious diseases. With the emergence of COVID-19, the interest in ACE2 models has intensified”. This sentiment encapsulates the ongoing quest to harness ACE2’s secrets, a journey in which each discovery brings us closer to combating some of the most pressing health challenges of our time.
