The Ang II/Rac1/STAT3 pathway is an important signaling pathway in the atrial myocardium to mediate atrial structural remodeling, and losartan and statin may be able to reverse Ang II-induced atrial structural remodeling in atrial fibrillation.

Abstract-Angiotensin II (Ang II) is involved in the pathogenesis of atrial fibrillation (AF). L-type calcium channel (LCC)expression is altered in AF remodeling. We investigated whether Ang II modulates LCC current through transcriptional regulation, by using murine atrial HL-1 cells, which have a spontaneous calcium transient, and an in vivo rat model. Ang II increased LCC ␣1C subunit mRNA and protein levels and LCC current density, which resulted in an augmented calcium transient in atrial myocytes. An Ϸ2-kb promoter region of LCC ␣1C subunit gene was cloned to the pGL3 luciferase vector. Ang II significantly increased promoter activity in a concentration-and time-dependent manner.Truncation and mutational analysis of the LCC ␣1C subunit gene promoter showed that cAMP response element (CRE) (Ϫ1853 to Ϫ1845) was an important cis element in Ang II-induced LCC ␣1C subunit gene expression. Transfection of dominant-negative CRE binding protein (CREB) (pCMV-CREBS133A) abolished the Ang II effect. Ang II (1 mol/L, 2 hours) induced serine 133 phosphorylation of CREB and binding of CREB to CRE and increased LCC ␣1C subunit gene promoter activity through a protein kinase C/NADPH oxidase/reactive oxygen species pathway, which was blocked by the Ang II type 1 receptor blocker losartan and the antioxidant simvastatin. In the rat model, Ang II infusion increased LCC ␣1C subunit expression and serine 133 phosphorylation of CREB, which were attenuated by oral losartan and simvastatin. In summary, Ang II induced LCC ␣1C subunit expression via a protein kinase C-, reactive oxygen species-, and CREB-dependent pathway and was blocked by losartan and simvastatin. [2][3][4] Moreover, blockade of the renin-angiotensin system has been shown to be an effective treatment of AF. 5 Ang II increases spontaneous calcium sparks 6,7 and L-type calcium channel (LCC) current (I CaL ) in cardiomyocytes. 7,8 However, downregulation of I CaL 9 and channel expression 10,11 are observed in AF. Whether Ang II increases or decreases I CaL channel subunit expression in atrial myocytes and the detailed signaling mechanisms are unknown. Accordingly, in the present study, we explored the chronic effect of Ang II on the transcriptional regulation of LCC channel subunits in atrial myocytes. We used a murine atrial cell line HL-1, which is the only available atrial myocyte cell line that continuously divides and maintains a differentiated cardiac phenotype with spontaneous depolarization. 10 We also used an in vivo rat model of Ang II infusion to verify the results obtained in the cellular study. We first found that Ang II increased LCC channel ␣1C subunit expression and augmented I CaL and calcium transient amplitude in HL-1 atrial myocytes. The detailed signaling mechanisms by which Ang II regulates the expression of LCC ␣1C subunits were also studied. Materials and Methods Culture and Transfection of HL-1 CardiomyocytesHL-1 myocytes were cultured in the Claycomb medium. Transient transfection of the HL-1 myocytes was performed using Lipo-

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Previous genome-wide association studies had identified single-nucleotide polymorphisms in several genomic regions to be associated with AF. In human genome, copy number variations (CNVs) are known to contribute to disease susceptibility. Using a genome-wide multistage approach to identify AF susceptibility CNVs, we here show a common 4,470-bp diallelic CNV in the first intron of potassium interacting channel 1 gene (KCNIP1) is strongly associated with AF in Taiwanese populations (odds ratio=2.27 for insertion allele; P=6.23 × 10−24). KCNIP1 insertion is associated with higher KCNIP1 mRNA expression. KCNIP1-encoded protein potassium interacting channel 1 (KCHIP1) is physically associated with potassium Kv channels and modulates atrial transient outward current in cardiac myocytes. Overexpression of KCNIP1 results in inducible AF in zebrafish. In conclusions, a common CNV in KCNIP1 gene is a genetic predictor of AF risk possibly pointing to a functional pathway.

The genetic architecture of subjects with extreme phenotypes of AF is similar to that of rare or Mendelian diseases, and mutations may be the underlying cause.

Whole-genome doubling (WGD) is an early macro-evolutionary event in tumorigenesis, involving the doubling of an entire chromosome complement. However, its impact on breast cancer subtypes remains unclear. Here, we performed a comprehensive and quantitative analysis of WGD and its influence on breast cancer subtypes in patients from Taiwan and consequently highlight the genomic association between WGD and homologous recombination deficiency (HRD). A higher manifestation of WGD was reported in triple-negative breast cancer, conferring high chromosomal instability (CIN), while HER2 + tumors exhibited early WGD events, with widely varied CIN levels, compared to luminal-type tumors. An association of higher activity of de novo indel signature 2 with WGD and HRD in Taiwanese breast cancer patients was reported. A control test between WGD and pseudo non-WGD samples was further employed to support this finding. The study provides a better comprehension of tumorigenesis in breast cancer subtypes, thus assisting in personalized treatment.