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Macrophage Reprogramming Induced by Hypertensive Stress Underlies Pathogenesis of Non-Obese Heart Failure with Preserved Ejection Fraction

ABSTRACT: Heart failure with preserved ejection fraction (HFpEF) is a leading cause of morbidity and mortality worldwide; nonetheless, effective therapies remain elusive. In Western populations, HFpEF is typically obesity-related, whereas in Asia it frequently develops in non-obese patients with hypertension and underlying mechanisms are poorly defined. Here, analysis of two Japanese hospital cohorts revealed that obesity and metabolic comorbidities are uncommon in HFpEF, while sympathetic overactivation and hypertension predominated. To model this condition, we combined isoproterenol (ISO)–induced sympathetic activation with L-arginine methyl ester (L-NAME)-induced endothelial dysfunction, establishing the first non-obese HFpEF mouse model. These mice exhibited hallmark HFpEF features, whereas ISO alone caused hypertensive heart disease (HHD) without HFpEF, indicating that a "second hit" is essential for HFpEF progression. HFpEF mice showed expansion and reprogramming of cardiac macrophages to Pla2g7⁺ phenotypes and fibroblast activation via PDGF signaling, as loss of Timd4⁺ resident macrophages impaired cardiomyocyte energetics due to diminished BMP signaling. These outcomes drove maladaptive remodeling and inflammation, which precedes HFpEF onset. Notably, inhibition of the inflammatory mediator ANGPTL2 attenuated cardiac inflammation and prevented HFpEF progression. Our findings identify hypertensive stress-induced macrophage reprogramming as a central mechanism of non-obese HFpEF and highlight cardiac inflammation as a promising therapeutic target.

ORGANISM(S): Mus musculus

PROVIDER: GSE308210 | GEO | 2026/07/27

REPOSITORIES: GEO

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Project description:Background: Heart failure with preserved ejection fraction (HFpEF) is increasingly acknowledged as a major public health concern due to its complex pathophysiology that involves neuroinflammation and sympathetic activation. The crosstalk between the heart and hypothalamic microglia in HFpEF, particularly the role of small extracellular vesicles (sEVs), remains insufficiently explored. Methods and Results: We constructed a HFpEF model in mice by combining a long-term high-fat diet with the nitric oxide synthase inhibitor L-NAME. These mice exhibited activation of microglia and hypothalamic inflammation. Microglia depletion with PLX3397 suppressed sympathetic activity and improved cardiac dysfunction in HFpEF. sEVs derived from the myocardium of HFpEF mice induced a pro-inflammatory M1 phenotype in microglia, leading to hypothalamic inflammation and sympathetic activation. Intraperitoneal injection of the sEVs biogenesis inhibitor GW4869 reversed these changes in HFpEF mice. Similar pathological changes were observed in BV2 microglia treated with sEVs isolated from palmitic acid-treated HL-1 cardiomyocytes. Bioinformatic and RT-qPCR analyses revealed a notable upregulation of miR-200c-3p in sEVs derived from both HFpEF myocardial tissue and palmitic acid- treated HL-1 cardiomyocytes, as well as in microglia. Cardiomyocyte-specific miR-200c-3p sponge inhibited microglial activation, hypothalamic inflammation and sympathetic activation in HFpEF mice. Conversely, miR-200c-3p mimic exacerbated pro-inflammatory responses in BV2, while miR-200c-3p inhibitor prevented the transition to a pro-inflammatory phenotype. The anti-inflammatory protein DUSP1 was validated as a potential downstream target of miR-200c-3p in microglia. Conclusions: Our study reveals that HFpEF prompts cardiomyocytes to release sEVs enriched with miR-200c-3p, leading to hypothalamic inflammation and evoking sympathetic outflow, which in turn exacerbates cardiac dysfunction. Focusing on sEV-mediated communication between cardiomyocytes and microglia may offer a new therapeutic approach for HFpEF.

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Macrophage Reprogramming Induced by Hypertensive Stress Underlies Pathogenesis of Non-Obese Heart Failure with Preserved Ejection Fraction

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