Apocinina reverte fibrose e disfunção elétrica cardíaca induzida pelo aumento sistêmico de MMP-2 em camundongos adultos

Abstract

Heart failure (HF) is characterized by the heart's inability to maintain adequate tissue blood flow, associated with deficits in contraction and relaxation, due to either an acute or chronic injurious event. Matrix metalloproteinase 2 (MMP-2) is linked to the pathogenesis and pathophysiology of HF, promoting proteolysis of contractile proteins and oxidative stress. Rescue therapies that directly or indirectly modulate MMP-2 activity could help improve cardiac remodeling and dysfunction. Apocynin inhibits NADPH oxidase, thereby attenuating oxidative stress. This study hypothesizes that apocynin can reverse cardiac remodeling and electrical dysfunction induced by MMP-2 by preventing oxidative imbalance. The aim of this study is to evaluate the effect of apocynin on oxidative imbalance and cardiac remodeling induced by systemic MMP-2 increase in adult mice. Adult male C57BL/6 mice were subjected to two experimental protocols. First, the animals underwent a time course protocol and were divided into two groups: the vehicle group received 0.9% saline via intraperitoneal (ip) injection, and the MMP-2 group received MMP-2 (150 ng/g body weight) via ip injection, for up to 4 weeks. Subsequently, a treatment protocol with apocynin was performed, starting 4 weeks after the cessation of MMP-2 administration. During this period, the animals were divided into four experimental groups: 1) vehicle (received water via gavage); 2) apocynin (50 mg/kg via gavage); 3) MMP-2 (received water via gavage); and 4) MMP-2 + apocynin (50 mg/kg via gavage). At the end of the protocols, all animals underwent electrocardiography, and then their hearts were collected for morphological and biochemical evaluation. During the time course, the MMP-2 group showed increased gelatinolytic activity, oxidative imbalance, fibrosis, decreased heart rate, along with increased RR, PQ, QT, and QTc intervals from the first week of administration, effects that persisted over the four weeks, even without MMP-2 administration. Treatment with apocynin reversed the increase in MMP-2 activity and expression in the heart, as well as oxidative imbalance, lipid peroxidation, hypertrophy, cardiac fibrosis, and electrical dysfunction. We conclude that systemic MMP-2 increase can promote cardiac remodeling through increased MMP-2 activity and expression in cardiac tissue, leading to redox imbalance and electrical dysfunction, and that apocynin treatment was able to reverse the effects induced by MMP-2, suggesting that these effects are dependent on oxidative imbalance and NADPH oxidase.