Fibroblast growth factor 21 (FGF21), a metabolic hormone with pleiotropic effects, is beneficial for various cardiac disorders. However, FGF21’s role in heart failure with preserved ejection fraction (HFpEF) remains unclear. Here, we show that elevated circulating FGF21 levels are negatively associated with cardiac diastolic function in patients with HFpEF. Global or adipose FGF21 deficiency exacerbates cardiac diastolic dysfunction and damage in high-fat diet (HFD) plus N^[w]-nitro-L-arginine methyl ester (L-NAME)-induced HFpEF mice, whereas these effects are notably reversed by FGF21 replenishment. Mechanistically, FGF21 enhances the production of adiponectin (APN), which in turn indirectly acts on cardiomyocytes, or FGF21 directly targets cardiomyocytes, to negatively regulate pyruvate dehydrogenase kinase 4 (PDK4) production by activating PI3K/AKT signals, then promoting mitochondrial bioenergetics. Additionally, APN deletion strikingly abrogates FGF21’s protective effects against HFpEF, while genetic PDK4 inactivation markedly mitigates HFpEF in mice. Thus, FGF21 protects against HFpEF via fine-tuning the multiorgan crosstalk among the adipose, liver, and heart.

BACKGROUND: BMP9 (bone morphogenetic protein 9) is a member of the TGF-β (transforming growth factor β) family of cytokines with pleiotropic effects on glucose metabolism, fibrosis, and lymphatic development. However, the role of BMP9 in myocardial infarction (MI) remains elusive. METHODS: The expressional profiles of BMP9 in cardiac tissues and plasma samples of subjects with MI were determined by immunoassay or immunoblot. The role of BMP9 in MI was determined by evaluating the impact of BMP9 deficiency and replenishment with adeno-associated virus–mediated BMP9 expression or recombinant human BMP9 protein in mice. RESULTS: We show that circulating BMP9 and its cardiac levels are markedly increased in humans and mice with MI and are negatively associated with cardiac function. It is important to note that BMP9 deficiency exacerbates left ventricular dysfunction, increases infarct size, and augments cardiac fibrosis in mice with MI. In contrast, replenishment of BMP9 significantly attenuates these adverse effects. We further demonstrate that BMP9 improves lymphatic drainage function, thereby leading to a decrease of cardiac edema. In addition, BMP9 increases the expression of mitochondrial DECR1 (2,4-dienoyl-CoA [coenzyme A] reductase 1), a rate-limiting enzyme involved in β-oxidation, which, in turn, promotes cardiac mitochondrial bioenergetics and mitigates MI-induced cardiomyocyte injury. Moreover, DECR1 deficiency exacerbates MI-induced cardiac damage in mice, whereas this adverse effect is restored by the treatment of adeno-associated virus–mediated DECR1. Consistently, DECR1 deletion abrogates the beneficial effect of BMP9 against MI-induced cardiomyopathy and cardiac damage in mice. CONCLUSIONS: These results suggest that BMP9 protects against MI by fine-tuning the multiorgan cross-talk among the liver, lymph, and the heart.

Background and Aims: Myocardial infarction (MI) is an ischaemic cardiovascular disease associated with increased morbidity and mortality. Previous studies have suggested that serine carboxypeptidase 1 (Scpep1) is involved in vascular diseases; however, its role in cardiac diseases remains unclear. This study aims to explore the role of Scpep1 in regulating cardiac homeostasis during MI. Methods: The impact of Scpep1 deficiency or cardiac-specific knock-down and Scpep1 overexpression on heart function was evaluated in mice with MI. Its downstream functional mediators of Scpep1 were elucidated using proteomic analysis and confirmed by employing loss- and gain-of-function strategies. Results: Circulating and cardiac Scpep1 levels were up-regulated in mice with MI. Genetic ablation or cardiac-specific knock-down of Scpep1 alleviated MI-induced cardiac dysfunction and damage in mice. In contrast, cardiac-specific Scpep1 overexpression aggravated these adverse effects. Mechanistically, Scpep1 exacerbated MI-induced cardiac dysfunction and damage by impaired mitochondrial bioenergetics via binding to Pex3 to promote its degradation, ultimately contributing to mitochondrial fission and apoptosis. Moreover, the expressional profiles of Scpep1 in plasma samples and heart tissues of patients with MI or ischaemic cardiomyopathy were in line with those observed in the mouse models. In addition, pharmaceutical inhibition of Scpep1 notably improved MI-induced cardiac dysfunction and damage by improving mitochondrial fragmentation and bioenergetics post-MI. Conclusions: Scpep1 deficiency mitigates MI by improving Pex3-mediated mitochondrial fission and subsequent cardiomyocyte apoptosis. Scpep1 constitutes a potential therapeutic target for attenuating MI.

BACKGROUND: PYGM (muscle glycogen phosphorylase), the rate-limiting enzyme in glycogenolysis, plays an indispensable role in maintaining cardiac energy metabolism. However, the role of PYGM in the pathogenesis of myocardial infarction (MI) remains unclear. METHODS: The expression profiles of PYGM in cardiac tissues and plasma samples from subjects with MI were assessed using immunoblotting. The role of PYGM in MI was determined by evaluating the effects of PYGM deficiency and its replenishment through adeno-associated virus–mediated PYGM expression in mice with MI. RESULTS: We found that circulating PYGM levels and their cardiac contents were significantly decreased in patients with MI, which was associated with impaired cardiac function. Loss of PYGM significantly exacerbated MI-induced cardiac dysfunction and damage in mice, and replenishment of PYGM profoundly reversed these adverse effects. Mechanistically, PYGM enhanced glycogenolysis by activating glycolysis and the pentose phosphate pathway, thereby improving cardiac energy homeostasis and mitigating oxidative stress. In addition, PYGM improved MI-induced autophagic flux obstacles and alleviated MI-induced cardiac damage by suppressing the expression of Thbs1 (thrombospondin-1). Moreover, genetic deficiency or pharmacological blockage of autophagy attenuated the protective effects of PYGM against MI-induced cardiac injury, and cardiac-specific knockdown of Thbs1 substantially improved the adverse impact of MI on cardiac dysfunction and damage in PYGM-null mice. CONCLUSIONS: PYGM safeguards against MI-induced myocardial injury by stimulating glycogenolysis and promoting autophagic flux, thus preserving myocardial energy homeostasis.

Diabetic foot ulcer (DFU) presents a major clinical challenge due to impaired healing mechanisms. Through the single-cell RNA sequencing of granulation tissue during wound repair, we identified distinct cellular alterations in DFU. Our analysis revealed an inflammatory monocyte axis involving CD14⁺CCL2⁺ and FCN1⁺CCR2⁺ subpopulations, coupled with an imbalance between diminished IL2RA⁺FOXP3⁺ regulatory T cells and expanded CD8⁺GZMK⁺ effector T cells. Fibroblast analysis showed a selective reduction in COL6A1⁺COL6A3⁺ and COL7A1⁺COL10A1⁺ subpopulations. Fluorescence imaging confirmed these transcriptional changes at the protein level. This comprehensive profiling of the DFU repair microenvironment uncovers specific immune-fibroblast interactions that may underlie healing impairment, offering new directions for targeted therapeutic development.