Observational clinical and ex vivo studies have established a strong association between atrial fibrillation and inflammation1. However, whether inflammation is the cause or the consequence of atrial fibrillation and which specific inflammatory mediators may increase the atria's susceptibility to fibrillation remain elusive. Here we provide experimental and clinical evidence for the mechanistic involvement of myeloperoxidase (MPO), a heme enzyme abundantly expressed by neutrophils, in the pathophysiology of atrial fibrillation. MPO-deficient mice pretreated with angiotensin II (AngII) to provoke leukocyte activation showed lower atrial tissue abundance of the MPO product 3-chlorotyrosine, reduced activity of matrix metalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrial electrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which was reversed when MPO was restored. Humans with atrial fibrillation had higher plasma concentrations of MPO and a larger MPO burden in right atrial tissue as compared to individuals devoid of atrial fibrillation. In the atria, MPO colocalized with markedly increased formation of 3-chlorotyrosine. Our data demonstrate that MPO is a crucial prerequisite for structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation.

High blood pressure is the leading risk factor for death worldwide. One of the hallmarks is a rise of peripheral vascular resistance, which largely depends on arteriole tone. Ca 2+ -activated chloride currents (CaCCs) in vascular smooth muscle cells (VSMCs) are candidates for increasing vascular contractility. We analyzed the vascular tree and identified substantial CaCCs in VSMCs of the aorta and carotid arteries. CaCCs were small or absent in VSMCs of medium-sized vessels such as mesenteric arteries and larger retinal arterioles. In small vessels of the retina, brain, and skeletal muscle, where contractile intermediate cells or pericytes gradually replace VSMCs, CaCCs were particularly large. Targeted disruption of the calcium-activated chloride channel TMEM16A, also known as ANO1, in VSMCs, intermediate cells, and pericytes eliminated CaCCs in all vessels studied. Mice lacking vascular TMEM16A had lower systemic blood pressure and a decreased hypertensive response following vasoconstrictor treatment. There was no difference in contractility of medium-sized mesenteric arteries; however, responsiveness of the aorta and small retinal arterioles to the vasoconstrictioninducing drug U46619 was reduced. TMEM16A also was required for peripheral blood vessel contractility, as the response to U46619 was attenuated in isolated perfused hind limbs from mutant mice. Out data suggest that TMEM16A plays a general role in arteriolar and capillary blood flow and is a promising target for the treatment of hypertension.

The mechanisms underlying cardiac automaticity are still incompletely understood and controversial. Here we report the complete conditional and time-controlled silencing of the "funny" current (If) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific If silencing caused altered [Ca2+]i release and Ca2+ handling in the sinoatrial node, impaired pacemaker activity, and symptoms reminiscent of severe human disease of pacemaking. The effects of If silencing critically depended on the activity of the autonomic nervous system. We were able to rescue the failure of impulse generation and conduction by additional genetic deletion of cardiac muscarinic G-protein-activated (GIRK4) channels in If-deficient mice without impairing heartbeat regulation. Our study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels, thus offering a new therapeutic strategy for the treatment of heart rhythm diseases.

Key pointsr The adrenal hormone aldosterone can stimulate K + secretion during hyperkalaemia and Na + reabsorption during hypovolaemia in the kidney.r Angiotensin II is thought to switch the physiological mode of action from K + excretion towards Na + retention, but how the regulation is achieved when angiotensin II levels are suppressed by high Na + intake remains unknown.r We report that both dietary K + depletion and dietary K + loading provoke renal Na + retention and increase blood pressure in Na + replete mice, but these occur through different renal kinase signalling and Na + transport pathways.r An angiotensin II-and aldosterone-independent activation of the sodium-chloride cotransporter NCC contributes to the blood pressure increase induced by K + depletion, whereas the hypertensive response to K + loading is dependent on neither aldosterone nor Na + transport via the epithelial sodium channel ENaC.r These findings imply a major impact of K + homeostasis on renal Na + handling in the Na + replete state and suggest a mechanism for the hypertensive effect of the Western diet (high Na + and low K + ) in humans.Abstract A network of kinases, including WNKs, SPAK and Sgk1, is critical for the independent regulation of K + and Na + transport in the distal nephron. Angiotensin II is thought to act as a key hormone in orchestrating these kinases to switch from K + secretion during hyperkalaemia to Na + reabsorption during intravascular volume depletion, thus keeping disturbances in electrolyte and blood pressure homeostasis at a minimum. It remains unclear, however, how K + and Na + transport are regulated during a high Na + intake, which is associated with suppressed angiotensin II levels and a high distal tubular Na + load. We therefore investigated the integrated blood pressure, renal, hormonal and gene and protein expression responses to large changes of K + intake in Na + replete mice. Both low and high K + intake increased blood pressure and caused Na + retention. Low K + intake was accompanied by an upregulation of the sodium-chloride cotransporter (NCC) and its activating kinase SPAK, and inhibition of NCC normalized blood pressure. Renal responses were unaffected by angiotensin AT1 receptor antagonism, indicating that low K + intake activates the distal nephron by an angiotensin-independent mode of action. High K + intake was associated with elevated plasma aldosterone concentrations and an upregulation of the epithelial sodium channel (ENaC) and its activating kinase Sgk1. Surprisingly, high K + intake increased blood pressure even during ENaC or mineralocorticoid receptor antagonism, suggesting the contribution of aldosterone-independent mechanisms. These findings show that in a Na + replete state, changes in K + intake induce specific molecular and functional adaptations in the distal nephron that cause a functional coupling of renal K + and Na + handling, resulting in Na + retention and high blood pressure when K + intake is either restricted or excessively increased.

The role of CXCR1, also known as fractalkine receptor, in hypertension is unknown. The present study determined the role of the fractalkine receptor CXCR1 in hypertensive renal and cardiac injury. Expression of CXCR1 was determined using CXCR1 mice that express a GFP reporter in CXCR1 cells. FACS analysis of leukocytes isolated from the kidney showed that 34% of CD45 cells expressed CXCR1. Dendritic cells were the majority of positive cells (67%) followed by macrophages (10%), NK cells (6%) and T cells (10%). Using confocal microscopy, the receptor was detected in the kidney only on infiltrating cells but not on resident renal cells. To evaluate the role of CXCR1 in hypertensive end-organ injury an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of Ang II (1.5 ng/g/min) and a high salt diet in wildtype (n=15) and CXCR1-deficient mice (n=18). CXCR1-deficiency reduced the number of renal dendritic cells and increased the numbers of renal CD11b/F4/80 macrophages and CD11b/Ly6G neutrophils in Ang II infused mice. Surprisingly, CXCR1-deficient mice exhibited increased albuminuria, glomerular injury and reduced podocyte density in spite of similar levels of arterial hypertension. In contrast, cardiac damage as assessed by increased heart weight, cardiac fibrosis and expression of fetal genes and matrix components was not different between both genotypes. Our findings suggest that CXCR1 exerts protective properties by modulating the invasion of inflammatory cells in hypertensive renal injury. CXCR1 inhibition should be avoided in hypertension because it may promote hypertensive renal injury.

Key pointsr Large conductance voltage-and Ca 2+ -activated K + channels (BK channels) require the ancillary subunit BKβ1 for normal function in smooth muscle, renal and adrenal tissues.r BK channels influence vascular tone and blood pressure in mice, and a gain-of-function BKβ1 polymorphism has been associated with low prevalence of diastolic hypertension in human population studies.r In this study, we genetically removed the BKβ1 gene in three different strains of mice and then restored BKβ1 expression selectively in smooth muscle to determine its tissue-specific contribution to blood pressure.r We show that loss of BKβ1 in smooth muscle cells robustly increases vascular tone, but blood pressure of mice lacking BKβ1 was increased, unaltered or decreased depending on the genetic background.r The results clarify the contested view that BK channel activity influences blood pressure by setting vascular tone and they shed light on the relative contribution of vascular and renal/adrenal BK channel activity to blood pressure levels.Abstract The large conductance voltage-and Ca 2+ -activated K + (BK) channel is an important determinant of vascular tone and contributes to blood pressure regulation. Both activities depend on the ancillary BKβ1 subunit. To determine the significance of smooth muscle BK channel activity for blood pressure regulation, we investigated the potential link between changes in arterial tone and altered blood pressure in BKβ1 knockout (BKβ1 −/− ) mice from three different genetically defined strains. While vascular tone was consistently increased in all BKβ1 −/− mice independent of genetic background, BKβ1 −/− strains exhibited increased (strain A), unaltered (strain B) or decreased (strain C) mean arterial blood pressures compared to their corresponding BKβ1 +/+ controls. In agreement with previous data on aldosterone regulation by renal/adrenal BK channel function, BKβ1 −/− strain A mice have increased plasma aldosterone and increased blood pressure. Consistently, blockade of mineralocorticoid receptors by spironolactone treatment reversibly restored the elevated blood pressure to the BKβ1 +/+ strain A level. In contrast, loss of BKβ1 did not affect plasma aldosterone in strain C mice. Smooth muscle-restricted restoration of BKβ1 expression increased blood pressure in BKβ1 −/− strain C mice, implying that impaired smooth muscle BK channel activity lowers blood pressure in these animals. We conclude that BK channel

A key finding supporting a causal role of the immune system in the pathogenesis of hypertension is the observation that RAG1 knockout mice on a C57Bl/6J background (B6.Rag1 −/ − ), which lack functional B and T cells, develop a much milder hypertensive response to Ang II (angiotensin II) than control C57Bl/6J mice. Here, we report that we never observed any Ang II resistance of B6.Rag1 −/− mice purchased directly from the Jackson Laboratory as early as 2009. B6.Rag1 −/− mice displayed nearly identical blood pressure increases monitored via radiotelemetry and hypertensive end-organ damage in response to different doses of Ang II and different levels of salt intake (0.02%, 0.3%, and 3% NaCl diet). Similarly, restoration of T-cell immunity by adoptive cell transfer did not affect the blood pressure response to Ang II in B6.Rag1 −/− mice. Full development of the hypertension-resistant phenotype in B6.Rag1 −/− mice appears to depend on the action of yet unidentified nongenetic modifiers in addition to the absence of functional T cells.

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