Pulmonary hypertension (PH) is characterized by increased pulmonary artery pressure and can lead to right heart failure. Parathyroid hormone (PTH) is secreted by the parathyroid gland and plays a crucial role in calcium homeostasis. PTH also acts on the cardiovascular system and affects cardiovascular prognosis. We hypothesized that PTH would play a potential role in the pathogenesis of PH. Serum PTH levels were measured in patients with PH or suspected PH who underwent evaluation using right heart catheterization. We assessed whether the regulation of PTH and the PTH1R (PTH receptor) affected PH in a hypoxia-induced PH mouse model and a Sugen/hypoxia-induced PH rat model. To examine PTH1R regulation and the direct effects of PTH, human pulmonary artery smooth muscle cells were cultured. In the clinical study, we found that serum PTH concentration was associated with both mean pulmonary artery pressure and pulmonary vascular resistance, with a cutoff PTH level of 46.0 pg/mL (68.2% sensitivity, 100% specificity) for predicting PH. In the PH animal models-Sugen/hypoxia rats and hypoxia mice-PTH treatment exacerbated right ventricular hypertrophy and right ventricular systolic pressure. Conversely, PTH reduction by parathyroidectomy attenuated right ventricular hypertrophy and reduced pulmonary vascular remodeling in Sugen/hypoxia rats. In vitro studies revealed that HIF1α (hypoxia-inducible factor-1 alpha) promoted the PTH1R. Moreover, knockdown of the PTH receptor in the lungs ameliorated PH in Sugen/hypoxia rats and hypoxia mice. Treatment with PTH increased proliferation and migration of pulmonary artery smooth muscle cells through the PTH receptor-β-arrestin-ERK (extracellular signal-regulated kinase) signaling axis. Our clinical and experimental data suggest a potential involvement of PTH/PTH1R signaling in the development and progression of PH, highlighting PTH1R as a possible therapeutic target for further investigation.

Cardiometabolic diseases (CMDs) refer to a broad spectrum of interconnected disorders, including heart attack, obesity, diabetes, atherosclerosis, and metabolic dysfunction-associated steatohepatitis, which represent the leading cause of mortality worldwide. In recent years, research on the role of gut microbiota in the pathogenesis of CMD has gradually shifted from correlation-based observations to mechanistic explorations. Within this context, microbial enzymes have gained increasing attention as key regulatory factors. These enzymes not only participate in the metabolic regulation of microorganisms themselves but also directly mediate host-microbe interactions, influencing the onset and progression of CMD. Specifically, microbial enzymes play a central role in CMD by modulating the homeostasis of key host metabolites such as cholesterol, generating bioactive molecules with metabolic and immunoregulatory functions, and participating in drug responses and the metabolic transformation of other xenobiotics. These enzymes provide novel and well-defined molecular targets for developing precision intervention strategies targeting the gut microbiota-such as enzyme replacement therapy, the design of enzyme agonists or inhibitors, and in vivo gene editing-thereby holding promise for advancing CMD prevention and treatment strategies toward greater specificity and controllability. This review systematically summarizes key microbial enzymes involved in the metabolism of endobiotics, including amino acids, peptides, and purines, and xenobiotics such as drugs, elucidating their specific mechanisms and functions in the development of CMD, strategies for mining these microbial enzymes, and the challenges and future of microbial enzyme-based interventions.

Atherosclerosis occurs preferentially in regions of disturbed fluid shear stress (FSS), whereas physiological laminar FSS protects against disease by suppressing endothelial inflammation. Proinflammatory versus anti-inflammatory programs are associated with glycolysis versus oxidative phosphorylation, respectively, but mechanisms are poorly understood. The TF (transcription factor) FOXO1 (forkhead box protein O1) is known to regulate endothelial metabolism and angiogenesis, but little is known about its role in endothelial inflammation. Endothelial cells were treated with cytokines or subjected to defined flow patterns in vitro using a parallel plate flow chamber. Immunofluorescence, RNA sequencing, and biochemical assays assessed FOXO1 localization, gene expression, and posttranslational modifications. In vivo experiments used FOXO1-floxed mice crossed with Bmx-CreERT2 for artery endothelial cell-specific FOXO1 knockout. Hyperlipidemia was induced via injection of PCSK9 (proprotein convertase subtilisin/kexin type 9) adeno-associated virus and high-cholesterol/high-fat diet to assess atherosclerosis. Oscillatory FSS and inflammatory cytokines induced whereas physiological FSS inhibited FOXO1 nuclear translocation. Depleting FOXO1 in endothelial cells upregulated the protective flow-responsive TFs KLF (Krüppel-like factor) 2/4 and reduced oscillatory FSS-induced inflammatory genes. Inhibition of FOXO1 nuclear translocation by physiological FSS is mediated via a KLF2-CDK2 (cell cycle-dependent kinase 2) pathway, with the latter phosphorylating FOXO1 at S249. Artery endothelial cell-specific deletion of FOXO1 significantly reduced atherosclerotic plaques in hyperlipidemic mice. Inhibition of glycolysis blocked oscillatory shear stress-induced FOXO1 nucleus translocation, while treatment with lactate promoted FOXO1 nuclear localization. These effects required lactyltransferase AARS1 (alanyl-tRNA synthetase 1) and correlated with FOXO1 lactylation. These findings identify FOXO1 as a key mediator linking atheroprone flow and endothelial inflammatory gene expression via lactate-driven lactylation and nuclear translocation, promoting atherosclerosis. Conversely, physiological FSS suppresses FOXO1 via KLF2-CDK2 signaling. These complementary pathways suggest potential new therapeutic targets for treating atherosclerotic cardiovascular disease.

Pathogenic cardiac hypertrophy, often driven by mechanical stress, is a leading cause of heart failure. However, effective therapeutic targets remain limited. TMC6 (transmembrane channel-like protein 6) is abundant in healthy myocardium but downregulated in hypertrophic hearts; its role in cardiac hypertrophy remains undefined. We combined cardiac-specific Tmc6 knockout mice subjected to transverse aortic constriction surgery, neonatal rat ventricular myocytes, and CRISPR/Cas9-edited human pluripotent stem cell-derived cardiomyocytes to assess hypertrophy and signaling readouts. Subcellular localization, protein-protein interaction, and competitive peptide assays were used to dissect the mechanism. Adeno-associated virus serotype 9 (AAV9)-cTnT (cardiac troponin T)-TMC6 was used for in vivo rescue. TMC6 deficiency increased cardiomyocyte size, fetal gene expression, and adverse remodeling in vivo and in vitro, whereas TMC6 overexpression blunted hypertrophic responses. Full-length TMC6 localized to the endoplasmic reticulum and bound CIB1 (calcium and integrin-binding protein 1) to sequester it in the endoplasmic reticulum, limiting CIB1 access to sarcolemmal Ca2+ microdomains required to scaffold calcineurin and activate NFAT (nuclear factor of activated T cells). A cell-permeable TMC6161-180 peptide competitively displaced CIB1 from TMC6 and augmented hypertrophy in wild-type but not Tmc6 knockout cardiomyocytes, indicating a dominant-negative mechanism. Therapeutically, AAV9-cTnT-TMC6 restored TMC6-CIB1 engagement, suppressed calcineurin/NFAT readouts, and improved function after pressure overload. TMC6 is an endogenous brake on pathological hypertrophy that restrains CIB1-calcineurin/NFAT signaling via endoplasmic reticulum sequestration of CIB1. Restoring full-length TMC6 mitigates pressure-overload remodeling, nominating the TMC6-CIB1 axis as a therapeutic target.

Pathological cardiac hypertrophy is a major risk factor for heart failure. PGK1 (phosphoglycerate kinase 1) plays an important role in cellular energy metabolism. However, the functions of PGK1 in cardiac hypertrophy remain largely unexplored. The expression and activity of PGK1, as well as its metabolite 3-phosphoglycerate, were examined in cardiac hypertrophy patients and mice subjected to transverse aortic constriction or Ang II (angiotensin II). Liquid chromatography-tandem mass spectrometry and co-immunoprecipitation analyses were used to identify the interacting proteins of PGK1. The potential effect of a PGK1 inhibitor CBR-470-1 was examined in a murine model of cardiac hypertrophy. The activation and upregulation of PGK1 were observed in myocardium tissues from mice and patients with cardiac hypertrophy. Cardiomyocyte-specific PGK1-deficiency alleviated cardiac hypertrophy and dysfunction in mice. Conversely, cardiomyocyte-specific PGK1 overexpression or infusion of 3-phosphoglycerate exacerbated cardiac hypertrophy. Mechanistically, PGK1 functioned as a protein kinase to stimulate phosphorylation of vimentin (Ser83), followed by FAK/Src-mediated phosphorylation of PI3K/Akt. The activated vimentin/PI3K/Akt signaling facilitated cardiomyocyte ferroptosis. Inhibition of PGK1 by CBR-470-1 prevented cardiac hypertrophy in cellular and animal models. Our findings highlight a critical role for PGK1 in myocardial hypertrophy, with downstream activation of the vimentin/PI3K/Akt/ferroptosis pathway.