The COVID-19 pandemic has catapulted scientific research into understanding the mechanisms behind the virus and its impact on human health. One key player in this narrative is the angiotensin-converting enzyme 2 (ACE2), identified as the receptor facilitating the virus's entry into human cells. The intricacies of ACE2's role in the human body and its implications for diseases, notably COVID-19, have been the subject of extensive research. A recent review article delves into various ACE2 mouse models employed to study cardiovascular, pulmonary, and infectious diseases, shedding light on their significance in advancing our knowledge about COVID-19 and potential therapeutic strategies.
ACE2 was initially discovered in 2000 as an enzyme capable of converting Angiotensin II (Ang-II) into Angiotensin 1-7, a process crucial for regulating blood pressure and maintaining cardiovascular health. Over the years, it became evident that ACE2 plays protective roles in many diseases, notably those affecting the cardiovascular and pulmonary systems. However, the arrival of COVID-19 brought to the forefront ACE2's function as the entry receptor for the SARS-CoV-2 virus, thus intertwining its biological significance with the ongoing global health crisis.
The relationship between ACE2 and COVID-19 is multifaceted. On the one hand, the virus exploits ACE2 to invade human cells, particularly those in the respiratory tract, leading to severe lung injuries. On the other hand, the downregulation of ACE2 during infection exacerbates inflammation and tissue damage, further complicating the disease. This dual role of ACE2 necessitates a deeper understanding of its functions, prompting researchers to develop various ACE2 mouse models to examine its implications in COVID-19 and other health conditions.
The review article highlights several genetically engineered mouse models, each designed to explore different aspects of ACE2's role in health and disease. These models include systemic or organ-specific deletion of ACE2, as well as overexpression of murine or human ACE2. For instance, the K18-hACE2 mouse model, where the human ACE2 gene is driven by the human cytokeratin 18 promoter, is notable for its ability to support SARS-CoV and SARS-CoV-2 binding, thereby mimicking the human infection scenario. This model has been instrumental in studying the virus's pathogenesis and testing potential antiviral therapies.
One experiment involving the K18-hACE2 mice entailed intranasal inoculation with SARS-CoV, resulting in rapid weight loss, labored breathing, and high mortality within seven days post-infection. Notably, these mice exhibited higher viral titers and widespread lung inflammation compared to their non-transgenic counterparts, underscoring the severity of the infection. This model's ability to mimic critical aspects of human COVID-19 makes it a valuable tool for researchers seeking to unravel the disease's complexities and develop effective treatments.
Similarly, the review discusses the CMV-hACE2 mouse model, where the ACE2 gene is driven by the cytomegalovirus immediate-early enhancer and the chicken β-actin promoter. This model has shown varying levels of hACE2 expression across different tissues, with high expression correlating with increased severity and mortality following SARS-CoV infection. Infected mice displayed elevated levels of cytokines in the lungs and brain, highlighting the immune system's role in disease progression. By providing insights into the immune response's contribution to COVID-19's pathogenesis, this model aids in identifying potential targets for immunomodulatory therapies .
In addition to these transgenic models, the article introduces ACE2 knockout (KO) models, which have helped clarify ACE2's protective roles in various diseases. For instance, ACE2 KO mice exhibited worse outcomes in models of acute lung injury and ischemia-reperfusion injury, emphasizing ACE2's significance in mitigating tissue damage and inflammation. Such findings are relevant for understanding conditions associated with severe COVID-19, where inflammation and tissue damage are prominent features. By elucidating the mechanisms through which ACE2 confers protection .
The review also highlights models where ACE2 expression is controlled by tissue-specific promoters, allowing for the study of ACE2's role in specific organs. For example, the Syn-hACE2 model uses a synapsin-1 promoter to drive ACE2 expression in the brain. This model has revealed that neuronal ACE2 expression can modulate autonomic function and protect against hypertension and cardiac hypertrophy. Another model, the HFH4-hACE2, targets ACE2 expression to the lung's ciliated epithelial cells, providing insights into respiratory infections and potential therapeutic approaches .
The broader implications of these findings are profound. Understanding ACE2's role in COVID-19 could lead to innovative treatments that either block the virus's entry into cells or mitigate the negative effects of ACE2 downregulation during infection. Moreover, these models offer a platform to explore ACE2's involvement in non-COVID-related conditions, potentially uncovering new therapeutic avenues for cardiovascular and pulmonary diseases.
Despite the promising insights gained from ACE2 mouse models, certain limitations must be addressed. For instance, variations in ACE2 expression levels among different models can influence the severity of observed phenotypes, complicating data interpretation. Moreover, the translatability of findings from mouse models to humans remains a critical consideration, given the physiological differences between species. Therefore, future research must focus on refining these models and validating their relevance to human disease .
Looking ahead, the potential for ACE2-targeted therapies in treating COVID-19 and other diseases is immense. Ongoing research aims to develop drugs that enhance ACE2's protective effects or inhibit its interaction with SARS-CoV-2. Additionally, gene therapy approaches that increase ACE2 expression or activity are being explored as potential treatments for hypertension, heart failure, and other conditions. As our understanding of ACE2 deepens, these strategies hold promise for improving health outcomes in diverse patient populations.
The review article underscores the urgency of continued research into ACE2's multifaceted roles. With the advent of advanced genetic engineering techniques and a growing repository of ACE2 mouse models, scientists are well-equipped to uncover the enzyme's full therapeutic potential. As one study in the review eloquently states, "the ACE2 mouse models discussed in this review provide valuable resources to study the mechanisms of coronavirus infection, including in at-risk patients with cardiovascular and metabolic diseases, as well as to identify therapeutic strategies to combat the COVID-19 pandemic".
