In Vivo Cardioprotection by Pitavastatin From Ischemic-reperfusion Injury Through Suppression of IKK/NF-κB and Upregulation of pAkt–e-NOS

Abstract

Recent studies have uncovered the beneficial effects of statin in cardiovascular diseases; however, the role of pitavastatin in ischemia-reperfusion (IR)-induced apoptosis and myocardial damage is not established. Therefore, in this study, we aim to investigate whether pitavastatin treatment attenuates myocardial IR injury via regulating oxidative stress, inflammation, apoptosis, and phosphorylated protein kinase B (pAkt) endothelial nitric oxide synthase (e-NOS) pathways. After the 14-day treatment with pitavastatin (0.16-0.64 mg·kg·d, po) or saline, rats were subjected to 45 minutes of ischemia by occluding the left anterior descending coronary artery and to 60 minutes of reperfusion to induce myocardial damage. Pitavastatin at a dose of 0.32 and 0.64 mg/kg significantly improved cardiac function as evidenced by the normalization of the mean arterial pressure, heart rate, ±LVdP/dtmax, and left ventricular end-diastolic pressure as compared with the IR control. Additionally, pitavastatin dose-dependently normalized myocardial antioxidants, lactate dehydrogenase, and thiobarbituric acid reactive substances along with decreased serum tumor necrosis factor-α level and creatine kinase isoenzyme-MB activity. Furthermore, pitavastatin enhanced pAkt, (p) e-NOS, Bcl-2, and suppressed IκB kinase/nuclear factor-kappa B, nitrotyrosine (NO inactivation product), Bax, and capases-3 protein expression in the heart. Morphological assessments of the IR-challenged myocardium showed that 0.32 and 0.64 mg/kg of pitavastatin decrease myocardial necrosis and inflammatory changes. Thus, pitavastatin reduced IR-induced infarction and dysfunction via the augmentation of endogenous antioxidant, suppression of IκB kinase/nuclear factor-kappa B, activation of pAkt-e-NOS, and/or decreased NO inactivation and apoptosis.

Cisplatin-Induced Nephrotoxicity in Rats: Modulatory Role of Simvastatin and Rosuvastatin against Apoptosis and Inflammation

“…Cisplatin is metabolically converted to a more potent toxin that causes DNA injury, mitochondrial DNA and respiration damage with activation of apoptotic pathways, and initiation of inflammatory responses (Miller et al, 2010). Significant elevation of myeloperoxidase (MPO) level in cisplatin nephrotoxicity has been observed along with pro-inflammatory cytokines; TNF-α, and IL-1β indicative of provoked inflammatory response as reported earlier (Amirshahrokhi and Khalili, 2015).…”

“…In accordance, others reported increases in serum creatinine, and blood urea nitrogen (Saleh and El-Demerdash, 2005;Shimeda et al, 2005;Palipoch et al, 2014). Regardless their lipid-lowering activities, some statins possess favorable effects on the cardiovascular system, immune system, oxidative damage, immune system, and vascular & renal functions (Davignon, 2004;Mason et al, 2004;Ray and Cannon, 2005;Akalin Ciftci et al, 2015). Previous data demonstrated the protective actions of statins on oxidative stress in the kidney and other different body organs (Iseri et al, 2007;Khoshnoud et al, 2011;Dashti-Khavidaki et al, 2013).…”

“…Further, SIM (2.4 μmol/kg i.p./day, 2 or 8 weeks) exhibited neuroprotective properties in a rat model of Huntington's disease (Patassini et al, 2008). Other studies demonstrated that statins increased Bcl-2 abundance and decreased apoptosis in vivo (Malik et al, 2011;Qin et al, 2012;Rajtik et al, 2012).…”

“…Many studies suggested that some of the clinical benefits of statins are far beyond their cholesterol-lowering activities (Munford, 2001;Takemoto and Liao, 2001;Shishehbor et al, 2003). Statins were shown to exert the so-called pleiotropic effects, which include beneficial effects on oxidative damage, immune system, thrombosis, inflammation, and vascular & renal functions (Davignon, 2004;Mason et al, 2004;Ray and Cannon, 2005). Statins' antioxidant effects have been thoroughly tested in many studies (Iseri et al, 2007;Dashti-Khavidaki et al, 2013;Akalin Ciftci et al, 2015).…”

Rosuvastatin Reloading before Cardiac Surgery with Cardiopulmonary Bypass

“…Unfortunately, neither myocardial PI3K nor Akt phosphorylation was assessed in the present study, thereby limiting the interpretation of the exact underlying mechanisms of statin-related PTEN activation. However, downstream phosphorylation of eNOS was elevated in both statin groups independent of recapture therapy suggesting other mechanisms of eNOS activation beyond myocardial PI3K-Akt such as activation of the extracellular signal-related kinase 1/2 (ERK) or direct inhibitory effects on the central proinflammatory transcription factor NFĸB [28]. …”