UNC5C upregulation is associated with pathological cardiac remodeling and atrial fibrillation susceptibility in spontaneously hypertensive rats

Atrial fibrillation (AF) is One of the most significant global health issues. Along with the health risks, it has many social impacts that are serious to families as well. The pathologic cardiac remodeling associated with AF caused by hypertension is an important factor contributing to the development and progression of AF, but how this is actually accomplished has yet to be completely understood. The purpose of this study was to explore the relationship between UNC5C expression and hypertension-associated AF. We found that there is a significant increase in UNC5C levels in right atrial appendage tissues from AF patients and spontaneously hypertensive rats (SHRs). The mendelian randomization (MR) analysis further indicated a positive association between genetically predicted UNC5C protein levels and AF risk. Cardiac-specific overexpression and knockdown of UNC5C was performed in SHRs using adeno-associated virus vectors (AAV). Overexpression of UNC5C was associated with increased AF susceptibility, higher blood pressure, and more pronounced pathological cardiac remodeling, including myocardial hypertrophy, elevated left atrial (LA) pressure, and diastolic dysfunction. Additional mechanistic studies demonstrated that changes in UNC5C expression were associated with alterations in phosphorylated proteins that are part of the CaMKII/ERK signaling pathway. Additionally, UNC5C knockdown, either in vitro or in vivo, decreased pathologic remodeling of the heart and the predisposition to AF; however, knocking down Netrin-1 had no effect on the decrease in UNC5C-induced hypertrophy of primary atrial myocytes. Collectively, these findings indicate that UNC5C upregulation is linked to pathological cardiac remodeling and AF susceptibility, and identify UNC5C as a potential target for AF prevention and therapeutic intervention.