Infecção aguda por Zika Vírus: impacto na função cardíaca e no tônus vascular - papel do eixo CCR5–COX–PGI2-PKA

Abstract

ZIKV infection causes significant neurological complications; however, its cardiovascular impacts remain poorly explored. This study aimed to evaluate cardiovascular changes and their mechanisms in mice infected with ZIKV. A129 mice (IFNα/βR-/-) were used and divided into control (MOCK) and infected groups (4×10³ PFU, intravenous). Data were collected at 3- and 5-days post-infection (dpi), including clinical score, body mass, blood count, viral load, pro-inflammatory mediators, vascular permeability, renal function, systolic blood pressure (SBP), electrocardiogram, CK-MB levels, cardiac function and contractility, calcium transients, and vascular reactivity. In congenital infection, pregnant females of the C57Bl/6J lineage were infected (1×10⁶ PFU, via i.p.) on the 5th day of gestation and the vascular reactivity of the offspring was evaluated at the 12th week of life. Results with p<0.05 were considered statistically significant. The results demonstrated that ZIKV infection reduced body mass at 3 and 5 dpi and caused a decrease in blood pressure at 3 dpi. Additionally, infected mice exhibited systemic inflammation, leukocytosis, and splenomegaly. ZIKV was detected in the plasma, heart, and aorta at 3 and 5 dpi, with increased levels of CCL5 and CCL2 in the aorta and CCL5 in the plasma. ZIKV infection caused impaired renal function and an increase in tubular and interstitial cells. The electrocardiogram revealed cardiac conduction block at 5 dpi, with prolonged P wave, PR and QT interval. Cardiac contractility was enhanced, reflected by increased left ventricular developed pressure (LVDP), positive and negative pressure derivative (dP/dT), cardiomyocyte fractional shortening, and calcium transients. The observed cardiac hypercontractility may represent an early stage of compensatory myocardial dysfunction, potentially transient, possibly induced by activation of the CCR5–COX–prostacyclin–PKA axis, which can promote calcium overload in the cytoplasm due to impaired SERCA/phospholamban function. In mice aorta, the infection resulted in hyporeactivity to phenylephrine (5 dpi), which was reversed by CCL5 receptor antagonism (CCR5 - Maraviroc). COX-1 and COX-2 inhibitors (Mofezolac and Celecoxib, respectively), a prostacyclin receptor antagonist (RO1138452), and a protein kinase A (PKA) inhibitor (KT-5720) also reversed the vascular hyporeactivity. It is suggested that vascular inflammation and hyporesponsiveness to phenylephrine were mediated by the CCR5–COX prostacyclin–PKA pathway, and pharmacological intervention reversed this vascular dysfunction. ZIKV infection did not impact vascular reactivity in adult females, suggesting hormonal protection. However, in congenital infection, offspring exhibited hyperresponsiveness to phenylephrine, indicating the possible involvement of distinct mechanisms such as oxidative stress via superoxide anion production. The results suggest that activation of the CCR5–COX–prostacyclin–PKA inflammatory and endothelial axis may impact not only vascular tone but also cardiac electrical and contractile function during the acute phase of infection. Thus, this study contributes to clarifying the still poorly explored pathogenic mechanisms of ZIKV infection, highlighting its impact on the cardiovascular system.