Molecular Insights Into SARS COV-2 Interaction With Cardiovascular Disease: Role of RAAS and MAPK Signaling

Figures

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  Figure 1. The RAAS balance between AngII/AT1-R and ACE2/Ang(1-7)/Ang(1-7)R axes. The former is enhanced in CVD conditions triggering various intracellular pathways via MAPK signaling, which ultimately leads to cardiac and vascular remodeling, endothelial dysfunction, and atherosclerosis. ACE2, on the other hand, decreases inflammation by countering the effect of the ACE/AngII/AT1-R axis. ACE2/Ang(1-7)/Ang(1-7)R signaling pathway not only ameliorates cellular proliferation, hypertrophy, oxidative stress, and vascular fibrosis but also reduces the activation of the downstream MAPK cascades. AT1-R activation triggers p38 MPAK-dependent ACE2 excision and shedding leading to a reduced cell surface expression. As demonstrated in other coronaviruses, SARS-CoV-2 replication might be enhanced as a result of increased MAPK activity downstream of AngII in CVD patients.

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  Figure 2. The MAPK pathway can be induced by several triggers in various cells within the context of CVDs. For example, pressure overload can cause hypertrophy in cardiomyocytes via the ERK1/2/GLUT pathway. Oxidized LDL triggers macrophage proliferation via ERK1/2/GM-CSF, which contributes to the development of atherosclerosis. All cells involved in atherosclerosis can release cytokines in an ERK1/2 dependent manner, which ultimately propel plaque and clot growth. Cytokines can subsequently enhance MMP9 production, which leads to plaque rupture and thrombosis. Meanwhile, coronaviruses have been shown to involve p38 MAPK, JNK, and MKK1/ERK1/2 pathways for viral pathogenesis. MKK1/ERK1/2 pathway also upregulates the protease furin, which is implicated in SARS-CoV-2 entry due to the unique furin-like S1/S2 cleavage site. It is worth examining if inhibition of MKK1/ERK1/2 mitigates production of SARS-CoV-2 viral progeny. On the other hand, SARS-CoV-2 can also amplify production of cytokines, which can worsen existing CVDs.