Circulation research最新文献

Background: Arterial thrombotic events constitute the leading cause of mortality in hypertension. Gut dysbiosis induces endothelial dysfunction and systemic inflammation, contributing to hypertension and its associated cardiovascular complications. Whether these dysbiotic microbiota metabolites in hypertension directly regulate platelet hyperactivation and thrombosis remains unclear.

Methods: Fecal microbiota transplantation, 16S rRNA sequencing, and untargeted metabolomics were performed using samples from patients with hypertension. In vivo FeCl₃-induced mesenteric arteriole thrombosis model, ex vivo microfluidic whole-blood perfusion assay, and in vitro platelet functional studies defined the functional effects of acetate on platelet activation. Moreover, platelet-specific Olfr78 (olfactory receptor 78)-deficient mice were employed to explore the underlying mechanisms of acetate on platelet activation.

Results: Transplantation with fecal microbiota from patients with hypertension enhanced in vivo FeCl₃-injured mesenteric arteriole thrombosis and ex vivo whole blood thrombus formation compared with fecal microbiota from healthy normotensive subjects. Untargeted metabolomics revealed that gut microbiota-derived acetate was decreased in patients with hypertension, and plasma acetate concentration negatively correlated with integrin αIIbβ3 activation and P-selectin exposure. Acetate demonstrated superior antiplatelet efficacy against ADP-induced aggregation, dense-granule secretion, α-granule secretion, and integrin αIIbβ3 activation than collagen or thrombin-induced platelet activation. Mechanistic studies using platelet-specific Olfr78^-/- mice revealed that acetate bound to and activated Olfr78, a receptor not previously reported to be expressed in platelets, to elevate cAMP level and activate PKA, thereby increasing p-VASP and decreasing Ca²⁺ mobilization as well as inactivating RhoA/ROCK2/MLC (myosin light chain) signaling to inhibit platelet activation. A high-fiber diet upregulated acetate/Olfr78 signaling in platelets to suppress microvascular thrombosis and protect against myocardial injury during myocardial infarction in mice.

Conclusions: Acetate is a negative regulator of platelet hyperreactivity and thrombus formation via the Olfr78 receptor, and acetate deficiency contributes to platelet hyperreactivity in hypertension. Lifestyle modifications, particularly high-fiber dietary intervention and acetate supplementation, exhibit potent antithrombotic effects in hypertension.

Background: Na_V (voltage-gated sodium) channels drive cardiac excitability. Although Na_V1.5 is the primary cardiac isoform, the composition and functional contributions of non-Na_V1.5 isoforms in the heart remain unclear.

Methods: Here, we developed a chemical-genetic mouse model (Na_V1.5^GX/GX) in which Na_V1.5 can be selectively and reversibly inhibited by acyl- and aryl-sulfonamide compounds (GX [acyl- and aryl-sulfonamide compounds typically denoted by the name GX-### and associated items] drugs). Cardiac activity was assessed by electrocardiograms in vivo, and optical mapping was used for imaging of ex vivo hearts. Whole-cell voltage-clamp in tandem with validated toxins and isoform-selective inhibitors were used to examine sodium current composition.

Results: Na_V1.5^GX/GX mice exhibited normal cardiac function at baseline, but acute GX drug administration caused profound conduction defects and arrhythmias. Whole-heart optical mapping revealed dose-dependent chamber-specific sensitivity to Na_V1.5 inhibition, with the right ventricle being the most sensitive, followed by the left ventricle, left atrium, and right atrium. Patch-clamp recordings of isolated cardiomyocytes with application of Na_V isoform-selective inhibitors showed that Na_V1.5 contributed 93% of sodium current in the left ventricle, 79% in the right ventricle, and 78% in the atria. Non-Na_V1.5 isoforms were differentially enriched across chambers: Na_V1.8 in the left ventricle, Na_V1.1/1.3 in the right ventricle, and Na_V1.2/1.6/1.7 in the atria.

Conclusions: These results reveal a surprising chamber-specific isoform landscape of cardiac sodium currents, which may underlie the right ventricular predominant phenotype of Brugada syndrome. These data highlight non-Na_V1.5 isoforms as potential mediators of chamber-specific cardiac pathologies and as pharmacological targets.

Background: Contractile dysfunction, hypertrophy, and cell death during heart failure are linked to altered Ca²⁺ handling and elevated levels of the hormone AngII (angiotensin II), which signals through G_q-coupled AT₁Rs (AngII type 1 receptors), initiating hydrolysis of phosphatidylinositol (4,5)-bisphosphate. Chronic elevation of AngII contributes to cardiac pathology, but the mechanisms linking sustained AngII signaling to heart dysfunction remain incompletely understood. Here, we demonstrate that chronic AngII exposure profoundly disrupts cardiac phosphoinositide (PI) homeostasis, triggering a cascade of cellular adaptations that ultimately impair cardiac function.

Methods: Mice received 1-week infusions of AngII, bisperoxovanadium 1,10 phenanthroline, both, or saline via osmotic minipumps. We used mass spectrometry, super-resolution microscopy, electrophysiology, confocal imaging, immunoblot, echocardiography, and histology to assess PI levels, Ca_V1.2 localization, Ca²⁺ handling, protein phosphorylation, cardiac function, and fibrosis.

Results: Chronic AngII infusion caused widespread PI imbalance, reducing PI, phosphatidylinositol (4,5)-bisphosphate, and phosphatidylinositol (3,4,5)-trisphosphate levels. Ca_V1.2 channels are redistributed from t-tubules to endosomal compartments. Despite reduced sarcolemmal channel expression, Ca²⁺ currents and transients were maintained through enhanced PKA (protein kinase A)-mediated and CaMKII (Ca²⁺/calmodulin-dependent protein kinase II)-mediated phosphorylation of Ca²⁺-handling proteins. However, this compensation proved insufficient as cardiac function progressively declined, marked by pathological hypertrophy, t-tubule disruption, and diastolic dysfunction. PTEN (phosphatase and tensin homolog) inhibition preserved Akt signaling and protected against cardiac dysfunction and fibrosis without preventing cellular remodeling or altered calcium handling.

Conclusions: These findings reveal a complex interplay between PI signaling, ion channel trafficking, and compensatory phospho-regulation in AngII-induced cardiac pathology. We establish phosphatidylinositol (3,4,5)-trisphosphate depletion as a critical link between chronic AngII signaling and cardiac dysfunction. The dissociation between persistent cellular remodeling and preserved organ function with PTEN inhibition reveals that cardioprotection occurs primarily through reduced fibrosis. PTEN inhibition, thus, emerges as a promising therapeutic strategy for heart failure associated with pathological renin-angiotensin system activation, with potential to complement existing therapies by targeting antifibrotic responses.

Background: Given the persistently high morbidity and mortality of heart failure (HF), targeting myocardial remodeling, particularly pathological hypertrophy and fibrosis, has become a major therapeutic priority. RhoA (Ras homolog gene family member A), a small GTPase governing cytoskeletal reorganization and cell migration, plays a pivotal role in this process. However, RhoA has long been considered undruggable because of its high-affinity binding to GDP/GTP and the absence of well-defined druggable pockets.

Methods: Structural analyses comparing RhoA-GTP and RhoA-GDP conformations, combined with surface plasmon resonance-based screening, were used to identify a RhoA inhibitor. The underlying mechanism was validated in cultured cells and 3-dimensional myocardial tissue models. Therapeutic efficacy was assessed across multiple species of HF models and supported by multiomics analyses linking RhoA activation to human HF. Key findings were further confirmed by multiplex immunohistochemistry and pulldown assays in human heart specimens.

Results: We identified an unrecognized cryptic pocket adjacent to GDP in RhoA. A natural product, AH001, selectively occupied this pocket and interacted with GDP, thereby stabilizing the interaction between RhoA and its endogenous inhibitor, RhoGDIα (Rho GDP-dissociation inhibitor 1). AH001 suppressed downstream signaling by reducing MRTFA (myocardin-related transcription factor A) nuclear translocation and downregulating fibrosis- and hypertrophy-related proteins. Moreover, AH001 disrupted pathological crosstalk between Mrtfa+ cardiomyocytes and fibroblasts. Consequently, AH001 markedly attenuated myocardial remodeling in multiple HF animal models, as well as in 3-dimensional myocardial tissue models.

Conclusions: These findings establish pharmacological inhibition of RhoA activation as a viable strategy to mitigate myocardial remodeling in HF and provide a conceptual framework for developing reversible inhibitors against previously undruggable small GTPases.