KCNQ5 Controls Perivascular Adipose Tissue-Mediated Vasodilation.

BACKGROUND: Small arteries exhibit resting tone, a partially contracted state that maintains arterial blood pressure. In arterial smooth muscle cells, potassium channels control contraction and relaxation. Perivascular adipose tissue (PVAT) has been shown to exert anticontractile effects on the blood vessels. However, the mechanisms by which PVAT signals small arteries, and their relevance remain largely unknown. We aimed to uncover key molecular components in adipose-vascular coupling. METHODS: A wide spectrum of genetic mouse models targeting Kcnq3, Kcnq4, and Kcnq5 genes (Kcnq3-/-, Kcnq4-/-, Kcnq5-/-, Kcnq5dn/dn, Kcnq4-/-/Kcnq5dn/dn, and Kcnq4-/-/Kcnq5-/-), telemetry blood pressure measurements, targeted lipidomics, RNA-Seq profiling, wire-myography, patch-clamp, and sharp-electrode membrane potential measurements was used. RESULTS: We show that PVAT causes smooth muscle cell KV7.5 family of voltage-gated potassium (K+) channels to hyperpolarize the membrane potential. This effect relaxes small arteries and regulates blood pressure. Oxygenation of polyunsaturated fats generates oxylipins, a superclass of lipid mediators. We identified numerous oxylipins released by PVAT, which potentiate vasodilatory action in small arteries by opening smooth muscle cell KV7.5 family of voltage-gated potassium (K+) channels. CONCLUSIONS: Our results reveal a key molecular function of the KV7.5 family of voltage-gated potassium (K+) channels in the adipose-vascular coupling, translating PVAT signals, particularly oxylipins, to the central physiological function of vasoregulation. This novel pathway opens new therapeutic perspectives.

Protocol for assessing myogenic tone and perfusion pressure in isolated mouse kidneys.

The isolated perfused kidney is a classic ex vivo preparation for studying renal physiology in general and vascular function. Here, we present a protocol for assessing myogenic tone in isolated mouse kidneys as well as vasodilatory and vasoconstrictive responses, expressed as perfusion pressure. We describe steps for pre-operative preparation, kidney and renal artery isolation, and connection of renal artery with glass cannula. We then detail how to measure pressure changes in perfused kidneys and the myogenic tone. For complete details on the use and execution of this protocol, please refer to Cui et al.1.

An inactivating human TRPC6 channel mutation without focal segmental glomerulosclerosis.

Transient receptor potential cation channel-6 (TRPC6) gene mutations cause familial focal segmental glomerulosclerosis (FSGS), which is inherited as an autosomal dominant disease. In patients with TRPC6-related FSGS, all mutations map to the N- or C-terminal TRPC6 protein domains. Thus far, the majority of TRPC6 mutations are missense resulting in increased or decreased calcium influx; however, the fundamental molecular mechanisms causing cell injury and kidney pathology are unclear. We report a novel heterozygous TRPC6 mutation (V691Kfs*) in a large kindred with no signs of FSGS despite a largely truncated TRPC6 protein. We studied the molecular effects of V691Kfs* TRPC6 mutant using the tridimensional cryo-EM structure of the tetrameric TRPC6 protein. The results indicated that V691 is localized at the pore-forming transmembrane region affecting the ion conduction pathway, and predicted that V691Kfs* causes closure of the ion-conducting pathway leading to channel inactivation. We assessed the impact of V691Kfs* and two previously reported TRPC6 disease mutants (P112Q and G757D) on calcium influx in cells. Our data show that the V691Kfs* fully inactivated the TRCP6 channel-specific calcium influx consistent with a complete loss-of-function phenotype. Furthermore, the V691Kfs* truncation exerted a dominant negative effect on the full-length TRPC6 proteins. In conclusion, the V691Kfs* non-functional truncated TRPC6 is not sufficient to cause FSGS. Our data corroborate recently characterized TRPC6 loss-of-function and gain-of-function mutants suggesting that one defective TRPC6 gene copy is not sufficient to cause FSGS. We underscore the importance of increased rather than reduced calcium influx through TRPC6 for podocyte cell death.

Quantifying the impact of gut microbiota on inflammation and hypertensive organ damage.

AIMS: Hypertension (HTN) can lead to heart and kidney damage. The gut microbiota has been linked to HTN, although it is difficult to estimate its significance due to the variety of other features known to influence HTN. In the present study, we used germ-free (GF) and colonized (COL) littermate mice to quantify the impact of microbial colonization on organ damage in HTN. METHODS AND RESULTS: 4-week-old male GF C57BL/6J littermates were randomized to remain GF or receive microbial colonization. HTN was induced by subcutaneous infusion with angiotensin (Ang) II (1.44 mg/kg/day) and 1% NaCl in the drinking water; sham-treated mice served as control. Renal damage was exacerbated in GF mice, whereas cardiac damage was more comparable between COL and GF, suggesting that the kidney is more sensitive to microbial influence. Multivariate analysis revealed a larger effect of HTN in GF mice. Serum metabolomics demonstrated that the colonization status influences circulating metabolites relevant to HTN. Importantly, GF mice were deficient in anti-inflammatory faecal short-chain fatty acids (SCFA). Flow cytometry showed that the microbiome has an impact on the induction of anti-hypertensive myeloid-derived suppressor cells and pro-inflammatory Th17 cells in HTN. In vitro inducibility of Th17 cells was significantly higher for cells isolated from GF than conventionally raised mice. CONCLUSION: The microbial colonization status of mice had potent effects on their phenotypic response to a hypertensive stimulus, and the kidney is a highly microbiota-susceptible target organ in HTN. The magnitude of the pathogenic response in GF mice underscores the role of the microbiome in mediating inflammation in HTN.

Nonstoichiometry, Defect Chemistry and Oxygen Transport in Fe-Doped Layered Double Perovskite Cobaltite PrBaCo2-xFexO6-δ (x = 0-0.6) Membrane Materials.

Mixed conducting cobaltites PrBaCo2-xFexO6-δ (x = 0-0.6) with a double perovskite structure are promising materials for ceramic semi-permeable membranes for oxygen separation and purification due to their fast oxygen exchange and diffusion capability. Here, we report the results of the detailed study of an interplay between the defect chemistry, oxygen nonstoichiometry and oxygen transport in these materials as a function of iron doping. We show that doping leads to a systematic variation of both the thermodynamics of defect formation reactions and oxygen transport properties. Thus, iron doping can be used to optimize the performance of mixed conducting oxygen-permeable double perovskite membrane materials.

Thermochemical Study of CH3NH3Pb(Cl1-xBrx)3 Solid Solutions.

Hybrid organic-inorganic perovskite halides, and, in particular, their mixed halide solid solutions, belong to a broad class of materials which appear promising for a wide range of potential applications in various optoelectronic devices. However, these materials are notorious for their stability issues, including their sensitivity to atmospheric oxygen and moisture as well as phase separation under illumination. The thermodynamic properties, such as enthalpy, entropy, and Gibbs free energy of mixing, of perovskite halide solid solutions are strongly required to shed some light on their stability. Herein, we report the results of an experimental thermochemical study of the CH3NH3Pb(Cl1-xBrx)3 mixed halides by solution calorimetry. Combining these results with molecular dynamics simulation revealed the complex and irregular shape of the compositional dependence of the mixing enthalpy to be the result of a complex interplay between the local lattice strain, hydrogen bonds, and energetics of these solid solutions.

In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome.

Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of pro-fibrotic markers (Col1α1, Col3α1, Col4α1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of intercellular adhesion molecule 1 (ICAM-1) and α-smooth muscle actin (α-SMA) were diminished in SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+ and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome.

Role of TRPC6 in kidney damage after acute ischemic kidney injury.

Transient receptor potential channel subfamily C, member 6 (TRPC6), a non-selective cation channel that controls influx of Ca2+ and other monovalent cations into cells, is widely expressed in the kidney. TRPC6 gene variations have been linked to chronic kidney disease but its role in acute kidney injury (AKI) is unknown. Here we aimed to investigate the putative role of TRPC6 channels in AKI. We used Trpc6-/- mice and pharmacological blockade (SH045 and BI-749327), to evaluate short-term AKI outcomes. Here, we demonstrate that neither Trpc6 deficiency nor pharmacological inhibition of TRPC6 influences the short-term outcomes of AKI. Serum markers, renal expression of epithelial damage markers, tubular injury, and renal inflammatory response assessed by the histological analysis were similar in wild-type mice compared to Trpc6-/- mice as well as in vehicle-treated versus SH045- or BI-749327-treated mice. In addition, we also found no effect of TRPC6 modulation on renal arterial myogenic tone by using blockers to perfuse isolated kidneys. Therefore, we conclude that TRPC6 does not play a role in the acute phase of AKI. Our results may have clinical implications for safety and health of humans with TRPC6 gene variations, with respect to mutated TRPC6 channels in the response of the kidney to acute ischemic stimuli.

Thermodynamics of Formation and Disordering of YBaCo2O6-δ Double Perovskite as a Base for Novel Dense Ceramic Membrane Materials.

Differential scanning calorimetry studies of the complex oxide YBaCo2O6-δ (YBC), combined with the literature data, allowed outlining the phase behavior of YBC depending on the oxygen content and temperature between 298 K and 773 K. The oxygen nonstoichiometry of single-phase tetragonal YBC was measured at different temperatures and oxygen partial pressures by both thermogravimetric and flow reactor methods. The defect structure of YBC was analyzed. As a result, the thermodynamic functions (∆Hi○, ∆Si○) of the defect reactions in YBC were determined. Experimental data on the oxygen content and those calculated based on the theoretical model were shown to be in good agreement. Standard enthalpies of formation at 298.15 K (∆Hf○) were obtained for YBC depending on its oxygen content using solution calorimetry. It was found that ∆Hf○ = f(6-δ) function is linear in the range of (6-δ) from 5.018 to 5.406 and that its slope is close to the value of the enthalpy of the quasichemical reaction describing oxygen exchange between the oxide and ambient atmosphere, which confirms the reliability of the suggested defect structure model.

Aging Affects KV7 Channels and Perivascular Adipose Tissue-Mediated Vascular Tone.

Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent KV7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, and QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography and membrane potential measurements with sharp electrodes. We also performed bulk RNA sequencing and quantitative reverse transcription-polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via KV7.3-5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, KV7.3-5 channels represent a promising target in cardiovascular aging.

Redox Thermochemistry, Thermodynamics, and Solar Energy Conversion and Storage Capability of Some Double Perovskite Cobaltites.

The oxygen nonstoichiometry, δ, and oxidation enthalpy, ΔHox, of double perovskites RBaCo2O6-δ (R = Sm or Eu) were simultaneously measured depending on the temperature and oxygen partial pressure, pO2. Theoretical equations for ΔHox(T, δ) and pO2(T, δ) were derived from the defect structure model based on the oxygen exchange and cobalt disproportionation reactions. These equations were fitted independently to each of the experimental ΔHox(T, δ) and pO2(T, δ) data sets. The resulting enthalpies of defect reactions were found to be almost the same irrespective of the calculation method. In other words, the models, describing satisfactorily the data, can be used to calculate both compositional dependences and redox thermodynamics of RBaCo2O6-δ (R = Sm or Eu). In addition, from the previously published data and the data presented here, trends were determined in the defect reaction thermodynamics of RBaCo2O6-δ (R = La, Pr, Nd, Sm, Eu, Gd, or Y). Drop calorimetric measurements were performed in air to obtain enthalpy increments for RBaCo2O6-δ (R = Sm or Eu) with variable oxygen content because the samples lost oxygen upon being heated in the calorimetric cell. As-obtained data were used to calculate the functional dependences of enthalpy increments of EuBaCo2O5.56 and SmBaCo2O5.6 with a constant oxygen content. In addition, as an example of practical application-oriented calculations for solar energy conversion and oxygen storage, the performances at equilibrium of RBaCo2O6-δ (R = Pr, Sm, Eu, or Gd) were evaluated and compared to those of SrFeO3-δ as a reference material.

Gausemycins†A,B: Cyclic Lipoglycopeptides from Streptomyces sp.*.

We report a novel family of natural lipoglycopeptides produced by Streptomyces sp. INA-Ac-5812. Two major components of the mixture, named gausemycins A and B, were isolated, and their structures were elucidated. The compounds are cyclic peptides with a unique peptide core and several remarkable structural features, including unusual positions of d-amino acids, lack of the Ca2+ -binding Asp-X-Asp-Gly (DXDG) motif, tyrosine glycosylation with arabinose, presence of 2-amino-4-hydroxy-4-phenylbutyric acid (Ahpb) and chlorinated kynurenine (ClKyn), and N-acylation of the ornithine side chain. Gausemycins have pronounced activity against Gram-positive bacteria. Mechanistic studies highlight significant differences compared to known glyco- and lipopeptides. Gausemycins exhibit only slight Ca2+ -dependence of activity and induce no pore formation at low concentrations. Moreover, there is no detectable accumulation of cell wall biosynthesis precursors under treatment with gausemycins.

Crucial Role of Water in the Mechanosynthesis of CsPbI3 and Other ABX3 Halides.

Mechanochemical synthesis of CsPbI3 , as a model system for ABX3 halides, was studied. Water was shown to strongly promote the kinetics of formation of CsPbI3 from the CsI+PbI2 mixture through increased mobility of the constituting ionic species. Since many binary and ternary halides are hygroscopic, it was concluded that the presence of small, uncontrollable and unintentional additions of water should often occur in both precursor mixtures and synthesized complex halides boosting the kinetics of formation of many, if not all, ternary organic-inorganic hybrid halides such as, for example, MAPbX3 (X=Cl, Br, I). In addition, trace amounts of water should influence the transport characteristics of complex halides. Thus, the presence of water explains, at least partially, the huge scatter in both the reported mechanochemical reaction times necessary for obtaining single-phase APbX3 perovskite halides and the activation energies of ionic diffusion in APbX3 .

Phosphodiesterase 3A and Arterial Hypertension.

BACKGROUND: High blood pressure is the primary risk factor for cardiovascular death worldwide. Autosomal dominant hypertension with brachydactyly clinically resembles salt-resistant essential hypertension and causes death by stroke before 50 years of age. We recently implicated the gene encoding phosphodiesterase 3A (PDE3A); however, in vivo modeling of the genetic defect and thus showing an involvement of mutant PDE3A is lacking. METHODS: We used genetic mapping, sequencing, transgenic technology, CRISPR-Cas9 gene editing, immunoblotting, and fluorescence resonance energy transfer. We identified new patients, performed extensive animal phenotyping, and explored new signaling pathways. RESULTS: We describe a novel mutation within a 15 base pair (bp) region of the PDE3A gene and define this segment as a mutational hotspot in hypertension with brachydactyly. The mutations cause an increase in enzyme activity. A CRISPR/Cas9-generated rat model, with a 9-bp deletion within the hotspot analogous to a human deletion, recapitulates hypertension with brachydactyly. In mice, mutant transgenic PDE3A overexpression in smooth muscle cells confirmed that mutant PDE3A causes hypertension. The mutant PDE3A enzymes display consistent changes in their phosphorylation and an increased interaction with the 14-3-3θ adaptor protein. This aberrant signaling is associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function. CONCLUSIONS: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance causing hypertension. We present 2 new animal models that will serve to elucidate the underlying mechanisms further. Our findings could facilitate the search for new antihypertensive treatments.

Age attenuates the T-type CaV 3.2-RyR axis in vascular smooth muscle.

Caveolae position CaV 3.2 (T-type Ca2+ channel encoded by the α-3.2 subunit) sufficiently close to RyR (ryanodine receptors) for extracellular Ca2+ influx to trigger Ca2+ sparks and large-conductance Ca2+ -activated K+ channel feedback in vascular smooth muscle. We hypothesize that this mechanism of Ca2+ spark generation is affected by age. Using smooth muscle cells (VSMCs) from mouse mesenteric arteries, we found that both Cav 3.2 channel inhibition by Ni2+ (50 µM) and caveolae disruption by methyl-ß-cyclodextrin or genetic abolition of Eps15 homology domain-containing protein (EHD2) inhibited Ca2+ sparks in cells from young (4 months) but not old (12 months) mice. In accordance, expression of Cav 3.2 channel was higher in mesenteric arteries from young than old mice. Similar effects were observed for caveolae density. Using SMAKO Cav 1.2-/- mice, caffeine (RyR activator) and thapsigargin (Ca2+ transport ATPase inhibitor), we found that sufficient SR Ca2+ load is a prerequisite for the CaV 3.2-RyR axis to generate Ca2+ sparks. We identified a fraction of Ca2+ sparks in aged VSMCs, which is sensitive to the TRP channel blocker Gd3+ (100 µM), but insensitive to CaV 1.2 and CaV 3.2 channel blockade. Our data demonstrate that the VSMC CaV 3.2-RyR axis is down-regulated by aging. This defective CaV 3.2-RyR coupling is counterbalanced by a Gd3+ sensitive Ca2+ pathway providing compensatory Ca2+ influx for triggering Ca2+ sparks in aged VSMCs.

Vasodilation of rat skeletal muscle arteries by the novel BK channel opener GoSlo is mediated by the simultaneous activation of BK and Kv 7 channels.

BACKGROUND AND PURPOSE: BK channels play important roles in various physiological and pathophysiological processes and thus have been the target of several drug development programmes focused on creating new efficacious BK channel openers, such as the GoSlo-SR compounds. However, the effect of GoSlo-SR compounds on vascular smooth muscle has not been studied. Therefore, we tested the hypothesis that GoSlo-SR compounds dilate arteries exclusively by activating BK channels. EXPERIMENTAL APPROACH: Experiments were performed on rat Gracilis muscle, saphenous, mesenteric and tail arteries using isobaric and isometric myography, sharp microelectrodes, digital droplet PCR and the patch-clamp technique. KEY RESULTS: GoSlo-SR compounds dilated isobaric and relaxed and hyperpolarised isometric vessel preparations and their effects were abolished after (a) functionally eliminating K+ channels by pre-constriction with 50 mM KCl or (b) blocking all K+ channels known to be expressed in vascular smooth muscle. However, these effects were not blocked when BK channels were inhibited. Surprisingly, the Kv 7 channel inhibitor XE991 reduced their effects considerably, but neither Kv 1 nor Kv 2 channel blockers altered the inhibitory effects of GoSlo-SR. However, the combined blockade of BK and Kv 7 channels abolished the GoSlo-SR-induced relaxation. GoSlo-SR compounds also activated Kv 7.4 and Kv 7.5 channels expressed in HEK 293 cells. CONCLUSION AND IMPLICATIONS: This study shows that GoSlo-SR compounds are effective relaxants in vascular smooth muscle and mediate their effects by a combined activation of BK and Kv 7.4/Kv 7.5 channels. Activation of Kv 1, Kv 2 or Kv 7.1 channels or other vasodilator pathways seems not to be involved.

Thermoelectric Behavior of BaZr0.9Y0.1O3-d Proton Conducting Electrolyte.

BaZr0.9Y0.1O3-δ (BZY10), a promising proton conducting material, exhibits p-type conduction under oxidative conditions. Holes in BZY10 are of the small polaron type. However, there is no clear understanding at which places in the lattice they are localized. The main objectives of this work were, therefore, to discuss the nature of electronic defects in BZY10 on the basis of the combined measurements of the thermo-EMF and conductivity. Total electrical conductivity and Seebeck coefficient of BZY10 were simultaneously studied depending on partial pressures of oxygen (pO2), water (pH2O) and temperature (T). The model equation for total conductivity and Seebeck coefficient derived on the basis of the proposed defect chemical approach was successfully fitted to the experimental data. Transference numbers of all the charge carriers in BZY10 were calculated. The heat of transport of oxide ions was found to be about one half the activation energy of their mobility, while that of protons was almost equal to the activation energy of their mobility. The results of the Seebeck coefficient modeling indicate that cation impurities, rather than oxygen sites, should be considered as a place of hole localization.

Distinguishing Between Biological and Technical Replicates in Hypertension Research on Isolated Arteries.

Perivascular adipose tissue (PVAT) is implicated in the pathophysiology of cardiovascular disease, especially in obese individuals in which the quantity of renal and visceral PVAT is markedly increased. The control of arterial tone by PVAT has emerged as a relatively new field of experimental hypertension research. The discovery of this prototype of vasoregulation has been mostly inferred from data obtained using wire myography. Currently, there is a major discussion on distinguishing between biological vs. technical replicates in biomedical studies, which resulted in numerous guidelines being published on planning studies and publishing data by societies, journals, and associations. Experimental study designs are determined depending on how the experimentator distinguishes between biological vs. technical replicates. These definitions determine the ultimate standards required for making submissions to certain journals. In this article, we examine possible outcomes of different experimental study designs on PVAT control of arterial tone using isolated arteries. Based on experimental data, we determine the sample size and power of statistical analyses for such experiments. We discuss whether n-values should correspond to the number of arterial rings and analyze the resulting effects if those numbers are averaged to provide a single N-value per animal, or whether the hierarchical statistical method represents an alternative for analyzing such kind of data. Our analyses show that that the data (logEC50) from (+) PVAT to (-) PVAT arteries are clustered. Intraclass correlation (ICC) was 31.4%. Moreover, it appeared that the hierarchical approach was better than regular statistical tests as the analyses revealed by a better goodness of fit (v2-2LL test). Based on our results, we propose to use at least three independent arterial rings from each from three animals or at least seven arterial rings from each from two animals for each group, i.e., (+) PVAT vs. (-) PVAT. Finally, we discuss a clinical situation where distinguishing between biological vs. technical replicates can lead to absurd situations in clinical decision makings. We conclude that discrimination between biological vs. technical replicates is helpful in experimental studies but is difficult to implement in everyday's clinical practice.

Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage.

BACKGROUND: Arterial hypertension and its organ sequelae show characteristics of T cell-mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study (Canakinumab Antiinflammatory Thrombosis Outcome Study) targeting interleukin-1ß demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays a pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFAs) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in 2 different mouse models of hypertensive cardiovascular damage. METHODS: To investigate the effect of SCFAs on hypertensive cardiac damage and atherosclerosis, wild-type NMRI or apolipoprotein E knockout-deficient mice received propionate (200 mmol/L) or control in the drinking water. To induce hypertension, wild-type NMRI mice were infused with angiotensin II (1.44 mg·kg-1·d-1 subcutaneous) for 14 days. To accelerate the development of atherosclerosis, apolipoprotein E knockout mice were infused with angiotensin II (0.72 mg·kg-1·d-1 subcutaneous) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell depletion using PC61 antibody was used to examine the mode of action of propionate. RESULTS: Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated angiotensin II-infused wild-type NMRI mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated apolipoprotein E knockout-deficient mice. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in wild-type NMRI mice. Cardioprotective effects of propionate were abrogated in regulatory T cell-depleted angiotensin II-infused mice, suggesting the effect is regulatory T cell-dependent. CONCLUSIONS: Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial nonpharmacological preventive strategy for patients with hypertensive cardiovascular disease.