Cilostazol Prevents Atrial Structural Remodeling through the MEK/ERK Pathway in a Canine Model of Atrial Tachycardia

Abstract

Objectives: Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. Atrial structural remodeling (ASR), particularly atrial fibrosis, is an important contributor to the AF substrate. This study aimed to investigate the preventive effects of the phosphodiesterase 3 inhibitor cilostazol on ASR and its potential molecular mechanisms in a canine model of rapid atrial pacing (RAP). Methods: Thirty dogs were assigned to sham (Sham), paced/ no treatment (Paced) and paced + cilostazol 5 mg/kg/day (Paced + cilo) groups, with 10 dogs in each group. RAP at 500 beats/min was maintained for 2 weeks, while the Sham group was instrumented without pacing. Cilostazol was provided orally during pacing. Western blotting, RT-PCR and pathology were used to assess ASR. Results: Cilostazol attenuated atrial interstitial fibrosis and structural remodeling in canines with RAP. MEK/ERK transduction pathway gene expression was upregulated in the Paced group compared with the Sham group. Cilostazol markedly alleviated these changes in the MEK/ERK pathway. Transforming growth factor-β₁ protein expression in the Paced group was significantly higher than in the Sham group (p < 0.01), and was significantly reduced by cilostazol (p < 0.01). Conclusions: Our findings suggest that cilostazol is beneficial for prevention and treatment in atrial tachycardia-induced ASR in a canine model of RAP.

Rosuvastatin, but not atorvastatin, enhances the antihypertensive effect of cilostazol in an acute model of hypertension

“…Due to its vasodilator effects, cilostazol is frequently recommended for peripheral vascular disease. Interestingly, extensive research has highlighted cilostazol beneficial effects on the heart and cardiovascular diseases as well as its ability to reduce AnII-induced elevated SBP (Reddy et al 2018 ; Sun et al 2009 ; Tsuchiya et al 2002 ; Z. Zhao et al 2016 ). Moreover, hypertension and hyperlipidemia are major risk factors for cardiovascular diseases that often coexist (Borghi et al 2022 ).…”

“…Cilostazol, a selective phosphodiesterase-III enzyme inhibitor, is well-known for vasodilator and antiplatelet activity and is frequently used for peripheral arterial diseases management (Reddy et al 2018 ). Several cardiovascular benefits have been reported upon cilostazol treatment including prevention of either pulmonary arterial hypertension, fatal arrhythmia, or tachycardia-induced atrial remodeling (Sun et al 2009 ; Tsuchiya et al 2002 ; Zhao et al 2016 ). Moreover, in angiotensin II (AnII) hypertensive mice, it effectively decreased elevated systolic blood pressure and alleviated heart failure with diastolic dysfunction (Reddy et al 2018 ).…”