An α1D-adrenergic receptor vaccine protects against HFpEF in mice

Heart failure with preserved ejection fraction (HFpEF) remains a global clinical challenge with high mortality and restricted therapeutic options. Persistent sympathetic nervous system (SNS) overactivation, systemic metabolic dysregulation, and chronic inflammation are hallmarks of HFpEF pathogenesis. We developed ADRQβ-004, a novel therapeutic vaccine targeting α1D-adrenergic receptor (α1D-AR), to evaluate its potential in mitigating HFpEF.

A "two-hit" HFpEF mouse model was established in 6-week-old male ApoE^-/- mice via high-fat diet and N^ω- nitro-L-arginine methyl ester administration for 17 weeks. Mice were subcutaneously immunized with five doses of ADRQβ-004. We comprehensively assessed blood pressure, glucose/lipid metabolism, diastolic function, and cardiac remodeling. Pericardial adipose tissue (PAT) was specifically analyzed via histology, RNA-seq, and biochemical assays. Furthermore, a monoclonal antibody (ADR-004) was employed in an adipocyte-cardiomyocyte co-culture system to elucidate the underlying molecular mechanisms. ADRQβ-004 elicited high and sustained titer of specific antibody, demonstrating robust immunogenicity. Vaccination significantly improved glucose tolerance, insulin sensitivity, and lipid profiles in HFpEF mice. Morphological and functional analyses revealed that ADRQβ-004 markedly attenuated left ventricular remodeling, diastolic dysfunction, and myocardial mitochondrial impairment. Notably, the vaccine suppressed PAT inflammation and metabolic dysfunction. Mechanistically, blockade of α1D-AR via ADR-004 activated the PPARβ/AMPK/PGC1-α signaling pathway in adipocytes, which subsequently modulated adipocyte-cardiomyocyte crosstalk, leading to enhanced myocardial mitochondrial function and improved HFpEF phenotypes.

The ADRQβ-004 vaccine ameliorates HFpEF by modulating adipocyte-cardiomyocyte crosstalk through the PPARβ/AMPK/PGC1-α pathway. These findings suggest that ADRQβ-004 may serve as a promising immunomodulatory strategy for HFpEF research.