Loss of Hepatic Angiotensinogen Attenuates Diastolic Dysfunction in Heart Failure with Preserved Ejection Fraction

Increased hepatic angiotensinogen (AGT) abundance leads to cardiac diastolic dysfunction via the AngII‐independent pathway. Liver‐derived AGT is internalized by LRP2 in cardiac endothelial cells, subsequently contributing to myocardial diastolic dysfunction by suppressing microvascular angiogenesis via inhibiting the GATA2/Pim3 pathway. In vivo 18β‐glycyrrhetinic acid infusion may be a promising approach targeting hepatic AGT for heart failure with preserved ejection fraction (HFpEF) therapy. Abstract Heart failure with preserved ejection fraction (HFpEF) is a prevalent complex syndrome characterized by diastolic dysfunction with limited therapeutic options. While the renin‐angiotensin system (RAS) is implicated in heart failure pathogenesis, the causal contribution of angiotensinogen (AGT), the unique precursor of the RAS, to HFpEF remains undefined. Using a two‐hits mouse HFpEF model (high‐fat diet + L‐NAME), consistent upregulation of hepatic and plasma AGT is identified in wild‐type mice of both sexes. Critically, hepatocyte‐specific AGT deletion directly ameliorated diastolic dysfunction in male and female HFpEF mice, whereas systemic angiotensin II blockade (losartan) failed to improve cardiac diastolic function. Mechanistically, hepatic AGT drove HFpEF through LRP2‐mediated internalization in cardiac endothelial cells, suppressing the GATA2/Pim3 signaling axis, which inhibited microvascular angiogenesis and ultimately exacerbated diastolic dysfunction. To validate therapeutic potential, it is demonstrated that 18β‐glycyrrhetinic acid – identified as a potent hepatic AGT inhibitor – significantly improved cardiac diastolic function in HFpEF mice. These findings establish hepatic AGT as a causal contributor to HFpEF pathogenesis and reveal its therapeutic targeting as a promising strategy. Increased hepatic angiotensinogen (AGT) abundance leads to cardiac diastolic dysfunction via the AngII-independent pathway. Liver-derived AGT is internalized by LRP2 in cardiac endothelial cells, subsequently contributing to myocardial diastolic dysfunction by suppressing microvascular angiogenesis via inhibiting the GATA2/Pim3 pathway. In vivo 18β-glycyrrhetinic acid infusion may be a promising approach targeting hepatic AGT for heart failure with preserved ejection fraction (HFpEF) therapy. Abstract Heart failure with preserved ejection fraction (HFpEF) is a prevalent complex syndrome characterized by diastolic dysfunction with limited therapeutic options. While the renin-angiotensin system (RAS) is implicated in heart failure pathogenesis, the causal contribution of angiotensinogen (AGT), the unique precursor of the RAS, to HFpEF remains undefined. Using a two-hits mouse HFpEF model (high-fat diet + L-NAME), consistent upregulation of hepatic and plasma AGT is identified in wild-type mice of both sexes. Critically, hepatocyte-specific AGT deletion directly ameliorated diastolic dysfunction in male and female HFpEF mice, whereas systemic angiotensin II blockade (losartan) failed to improve cardiac diastolic function. Mechanistically, hepatic AGT drove HFpEF through LRP2-mediated internalization in cardiac endothelial cells, suppressing the GATA2/Pim3 signaling axis, which inhibited microvascular angiogenesis and ultimately exacerbated diastolic dysfunction. To validate therapeutic potential, it is demonstrated that 18β-glycyrrhetinic acid – identified as a potent hepatic AGT inhibitor – significantly improved cardiac diastolic function in HFpEF mice. These findings establish hepatic AGT as a causal contributor to HFpEF pathogenesis and reveal its therapeutic targeting as a promising strategy. Advanced Science, Volume 12, Issue 43, November 20, 2025.