Circulation research最新文献

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.

Background: Sex and atherosclerotic plaque histology are intertwined, with fibrous plaques being more prevalent in women. Plaque erosion, a significant contributor to acute coronary syndromes, is linked to fibrous plaques and is more prevalent in women than men. We hypothesize that the molecular drivers of histologically determined fibrous plaques differ between men and women.

Methods: Human end-stage atherosclerotic plaques were isolated from carotid endarterectomy patients included in the Athero-Express Biobank. Fibrous plaques were histologically assessed, linked to clinical characteristics, and processed for protein, bulk RNA, single-cell RNA, and DNA methylation data. We leveraged sex-differential gene expression and deconvolution analyses to uncover sex-biased molecular and cellular mechanisms. Spatial transcriptomics localized gene expression patterns in plaques. Furthermore, we studied the female-biased processes in human plaque endothelial cells and vascular smooth muscle cells stimulated with TGF-β (transforming growth factor-β), with or without SMAD3 (SMAD family member 3) inhibition.

Results: Of 1889 atherosclerotic plaques (1309 male and 580 female), fibrous lesions were observed in 50% of female and 31% of male patients. Compared with patients with atheromatous plaques (n=494), women with fibrous plaques exhibited a high prevalence of smoking, while men with fibrous plaques presented more often with diabetes. Female fibrous plaques were characterized by smooth muscle cell-driven ECM (extracellular matrix) remodeling, TGF-β response, and endothelial-to-mesenchymal transition, localized to the fibrous cap. Conversely, male plaques were linked to macrophage-mediated inflammation proximal to the core, dependent on diabetes. Finally, we experimentally confirmed these female-biased mechanisms, showing that TGF-β induced endothelial-to-mesenchymal transition in endothelial cells and ECM remodeling in vascular smooth muscle cells, both partly reversed by SMAD3 inhibition.

Conclusions: Women and men with end-stage fibrous atherosclerotic plaques exhibit distinct clinical and molecular profiles. These mechanisms might be candidate pathways to understand plaque erosion from a molecular point of view and may provide promising targets for atherosclerosis therapies, as they account for both sex and plaque phenotype.

Background: Lmods (leiomodins) are critical for the assembly and maintenance of thin filaments in striated muscles by allowing thin filament elongation at the pointed ends. Lmod2's elongation function has been linked to both actin-binding sites (ABSs) 2 and 3, while the existence and function of an N-terminal ABS1 has been debated.

Methods: To elucidate the little-known role of Lmod2's ABS1, we created a mutant (F64D/L69D/W72D/W73D: Lmod2-quadruple mutant) predicted to decrease the binding of ABS1 to actin. We analyzed the effect of the mutations using several in vitro, cellular, and in vivo assays.

Results: By disrupting the interaction of Lmod2 ABS1 with actin in isolated cardiomyocytes and in mice, we engineered a super Lmod2 that results in remarkably longer thin filaments. Structural analysis determined that ABS1 of Lmod2 binds to actin through a disordered region and an amphipathic α-helix. Analysis of the mutated ABS1 revealed that the helix is destroyed, and binding to actin is maintained only in the N-terminal disordered region of Lmod2 ABS1.

Conclusions: These discoveries support a model of controlled thin filament pointed end elongation by Lmod2 and provide the first direct evidence of, as well as the structural and functional mechanistic basis for, Lmod2's physiological leaky cap activity.