Targeting ACE2 in the Renin–Angiotensin–Aldosterone System: Post-COVID (Long-Term) Cardiovascular Sequelae

Q: What is the clinical evidence from this study?

Study design: Review. Population: Cardiovascular disease and post-COVID-19 cardiovascular sequelae. Intervention: Therapeutic strategies and natural products targeting the ACE2/angiotensin-(1-7)/Mas receptor axis.

Omotayo Alaba Eluwole; Oluwadare Ogunlade

doi:10.64253/042026jept002

June 15, 2026Journal of Experimental Pharmacology and ToxicologyOpen Access

Targeting ACE2 in the Renin–Angiotensin–Aldosterone System: Post-COVID (Long-Term) Cardiovascular Sequelae

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Key result

Targeting the ACE2-Mas axis counters RAAS dysregulation and offers potential cardioprotection after COVID-19.

Why the study?

Traditional RAAS therapies inhibit the classical ACE/Ang II/AT1 receptor axis, whereas SARS-CoV-2 downregulates the counter-regulatory ACE2/angiotensin-(1–7)/Mas receptor pathway, contributing to cardiovascular injury and post-COVID-19 complications. This review evaluates classical and alternative RAAS signaling and emerging therapies targeting the ACE2 axis.

Key Points

To review classical and counter-regulatory renin–angiotensin–aldosterone system pathways and evaluate ACE2-targeted therapeutic strategies for managing cardiovascular and post-COVID-19 complications.
Narrative review synthesizing molecular mechanisms of classical ACE/Ang II/AT1 receptor and alternative ACE2/Ang-(1–7)/Mas receptor signaling pathways.
Evaluated preclinical and clinical evidence on SARS-CoV-2-mediated ACE2 downregulation, cardiovascular injury, and emerging therapeutic modalities, including natural products.
ACE2 converts Ang II to angiotensin-(1–7), activating Mas receptors to promote vasodilation, reduce oxidative stress via lower NOX2 activity, and suppress inflammatory cytokines.
SARS-CoV-2-induced downregulation of ACE2 disrupts the counter-regulatory pathway, increasing Ang II and promoting epicardial adipose tissue inflammation and myocardial remodeling.
Evidence supporting ACE2/angiotensin-(1–7)/Mas axis modulation and phytochemical interventions remains predominantly preclinical, constrained by variable outcomes and a lack of standardized human trials.

Structured PICO

P

Population

Patients with cardiovascular diseases (such as hypertension, heart failure, and ischemic heart disease) and post-COVID-19 (long-term) cardiovascular sequelae (narrative review of English-language literature from 2012 to January 2026).

I

Intervention

Therapeutic strategies targeting the alternative RAAS pathway (ACE2/angiotensin-(1-7)/Mas receptor axis), including ACEIs, ARBs, ACE2 activators (xanthenone, diminazene aceturate), apelin analogs, SGLT2 inhibitors (dapagliflozin), and phytochemicals/medicinal plant extracts (flavonoids, polyphenols, terpenoids, saponins).

O

Outcome

Cardioprotection, modulation of RAAS balance (vasodilation, anti-inflammatory, antifibrotic, and antioxidative effects), and mitigation of post-COVID-19 cardiovascular complications.

This narrative review highlights how SARS-CoV-2-induced ACE2 downregulation drives long-term cardiovascular sequelae via unopposed Ang II signaling and evaluates the preclinical potential of targeting the counter-regulatory ACE2/Ang-(1-7)/Mas receptor axis with pharmacological and phytochemical agents.

Limitations

Much of the mechanistic evidence supporting ACE2-mediated cardioprotection and phytochemical modulation is derived from experimental, in vitro, and animal studies, with limited large-scale clinical validation in humans.
Variability in ACE2 expression across populations, disease states, and therapeutic exposures complicates translating findings into clinical practice.
Variability in bioavailability, dosing, and phytochemical composition of plant extracts complicates translation into therapeutic applications.
Potential interactions between phytochemicals and conventional RAAS-targeting drugs remain insufficiently explored.
Limited data from sub-Saharan Africa due to poor reporting infrastructure and healthcare-seeking behaviors.
Much of the mechanistic evidence supporting ACE2-mediated cardioprotection is derived from experimental and animal studies, with limited large-scale clinical validation.
Preclinical studies supporting phytochemical modulation of RAAS components have limited clinical trials validating efficacy and safety in humans, alongside variability in bioavailability, dosing, and composition.
Potential interactions between natural products and conventional RAAS-targeting drugs remain insufficiently explored.
Paucity of data from sub-Saharan Africa due to poor reporting infrastructure and healthcare-seeking behaviors.

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Implication

ACE2/Mas axis modulation may confer post-COVID cardioprotection; leaves open confirmation in standardized human trials.

Abstract

Cardiovascular diseases (CVDs) and the coronavirus disease 2019 (COVID-19) pandemic represent major, interrelated global health challenges, largely mediated by dysregulation of the renin–angiotensin–aldosterone system (RAAS). Traditionally, therapeutic strategies have focused on inhibiting the classical ACE/angiotensin II (Ang II)/AT1 receptor axis, which drives vasoconstriction, inflammation, fibrosis, and cardiovascular remodeling. However, the discovery of angiotensin-converting enzyme 2 (ACE2) has revealed an alternative, counter-regulatory RAAS pathway with significant physiological and therapeutic relevance, particularly in the context of COVID-19. ACE2 catalyzes the conversion of Ang II to angiotensin-(1–7), thereby activating the Mas receptor axis, which exerts vasodilatory, anti-inflammatory, antifibrotic, and antioxidative effects. SARS-CoV-2-induced downregulation of ACE2 disrupts this protective pathway, contributing to cardiovascular injury and post-COVID-19 complications. This review examines classical and alternative RAAS signaling, elucidates the molecular basis of ACE2-mediated cardioprotection, and critically evaluates emerging therapeutic strategies, including natural products targeting the ACE2/angiotensin-(1–7)/Mas receptor axis in cardiovascular disease and post-COVID-19 complications.

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Cite This Study

Eluwole et al. (2026) conducted a review in Cardiovascular disease and post-COVID-19 cardiovascular sequelae. Therapeutic strategies and natural products targeting the ACE2/angiotensin-(1-7)/Mas receptor axis was evaluated. Targeting the ACE2/angiotensin-(1-7)/Mas receptor axis counters classical RAAS dysregulation and offers potential cardioprotection against post-COVID-19 cardiovascular sequelae.

synapsesocial.com/papers/6af0e999de503f3774140a08 https://doi.org/10.64253/042026jept002

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Targeting ACE2 in the Renin–Angiotensin–Aldosterone System: Post-COVID (Long-Term) Cardiovascular Sequelae

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Targeting ACE2 in the Renin–Angiotensin–Aldosterone System: Post-COVID (Long-Term) Cardiovascular Sequelae

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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