An ACE-dependent increase in the amounts of activated Erk1/Erk2 in atrial interstitial cells may contribute as a molecular mechanism for the development of atrial fibrosis in patients with AF. These findings may have important impact on the treatment of AF.

Atrial fibrillation is associated with the fibrosis of subepicardial fatty infiltrates, a process in which cytotoxic lymphocytes might be involved. This remodelling of the atrial subepicardium could contribute to structural remodelling forming a substrate for AF.

The present study demonstrates that estrogen affects the human atrial myocardium and mediates protective actions through estrogen receptors-(ER) dependent signaling. Estrogen substantially modulates the local RAS via downregulation of ACE and simultaneous upregulation of ACE2, AT2R and MAS expression levels. This is indicative of a shift of the classical RAS/ACE axis to the alternative, protective RAS/ACE2 axis. In support of this view, estrogen attenuated the expression of RAS-associated downstream effectors, LOX-1, and ICAM-1. A specific antagonist of ERa reversed the anti-inflammatory and anti-oxidative effects of estrogen in paced and nonpaced atrial tissue slices. In summary, our data demonstrate the existence of protective effects of estrogen in atrial tissue from elderly men which are at least in part, mediated by the regulation of local RAS homeostasis. AbstractData from animal experiments and clinical investigations suggest that components of the renin-angiotensin system are markedly affected by sex hormones. However, whether estrogen affects human atrial myocardium has not been investigated yet. In this study, we determined the effects of estrogen on key components of atrial renin-angiotensin system: angiotensin-converting enzyme, responsible for generation of angiotensin II and angiotensin-converting enzyme 2, counteracting majority of AngII effects, and different renin-angiotensin system receptors, AT1R, AT2R, and MAS. First, the expression levels of estrogen receptors mRNA were determined in right atrial appendages obtained from patients undergoing heart surgery. The amounts of estrogen receptor a and estrogen receptor b mRNA were similar between women (n ¼ 14) and men (n ¼ 10). Atrial tissue slices (350 mm) were prepared from male donors which were exposed to estrogen (1-100 nM; n ¼ 21) or stimulated at 4 Hz for 24 h in the presence or absence of 100 nM estrogen (n ¼ 16), respectively. The administration of estrogen did not change mRNA levels of estrogen receptors, but activated MAP kinases, Erk1/2. Furthermore, estrogen increased the amounts of angiotensin-converting enzyme 2-mRNA (1.89 AE 0.23; P < 0.05) but reduced that of angiotensin-converting enzyme-mRNA (0.78 AE 0.07, P < 0.05). In addition, the transcript levels of AT2R and MAS were upregulated by estrogen. Pacing of tissue slices significantly increased the angiotensin-converting enzyme/angiotensin-converting enzyme 2 ratio at both the mRNA and protein level. During pacing, administration of estrogen substantially lowered the angiotensin-converting enzyme/angiotensin-converting enzyme 2 ratio at the transcript (0.92 AE 0.21 vs. 2.12 AE 0.27 at 4 Hz) and protein level (0.94 AE 0.20 vs. 2.14 AE 0.3 at 4 Hz). Moreover, estrogen elicited anti-inflammatory and anti-oxidative effects on renin-angiotensin system-associated downstream effectors such as pro-oxidative LOX-1 and pro-inflammatory ICAM-1. An antagonist of estrogen receptor a reversed these anti-inflammatory and anti-oxidative effects of estrogen significantly. Overall, our results demo...

AF is associated with the down-regulation of atrial AT(1)-R and the up-regulation of AT(2)-R proteins. These findings may help define the pathophysiological role of the angiotensin system in the structural remodeling of the fibrillating atria.

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10−10). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10–7) and 13% for RAB38/CTSC (P = 5.8 × 10−7). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.