High-salt diet in Dahl rats induced HFpEF evidenced by ~0.7-fold decrease in E/A ratio, ~1.3-fold increase in E deceleration time and IVRT, ~2.5-fold increase in LV end-diastolic pressure, and ~1.3-fold increase in cardiac fibrosis compared to low-salt controls.
Impaired adenosine metabolism and receptor signaling contribute to HFpEF progression, and selective A2A activation may offer a therapeutic target by attenuating endothelial pro-fibrotic profiles and restoring antioxidant defenses.
p-value: p<0.05 to p<0.0001 reported for differences in individual parameters vs controls
Introduction Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and lacks effective therapies. Key features of HFpEF include endothelial dysfunction, fibrosis, and oxidative stress. Adenosine signaling, regulated by enzymes and receptors, is critical for vascular homeostasis and inflammation, but its role in HFpEF remains poorly understood. Adenosine receptors are abundantly expressed in the heart and kidney, modulating vascular, fibrotic, and tubular processes. Dysregulation of adenosine pathways in either organ may drive hypertension, microvascular dysfunction, and maladaptive cardio-renal crosstalk, highlighting the need to investigate adenosine signaling as a combined multi-organ target. Methods HFpEF was induced in Dahl salt-sensitive rats by high-salt diet. Cardiac structure, function, fibrosis, oxidative stress, cytokines, renal adenosine receptors and cardiac adenosine pathway components were assessed using echocardiography, histology, proteome profiling and Western blotting. Human cardiac microvascular endothelial cells were treated with endothelin-1 in the presence of selective A 2A or A 2B agonists, or adenosine deaminase (ADA) inhibition, and profibrotic/oxidative stress genes were analyzed by qPCR. Results Hypertensive rats exhibited diastolic dysfunction with preserved systolic function, cardiac and renal fibrosis, oxidative/nitrative stress, and elevated pro-inflammatory cytokines. Cardiac expression of CD39, CD73, and ADA enzymes was significantly reduced, indicating impaired adenosine metabolism, while transporters ENT2 and CNT2 were also downregulated, reflecting impairment of both equilibrative and concentrative adenosine transport. Adenosine receptor profiles were altered: A 1 expression increased, A 2A decreased, and A 2B and A 3 selectively upregulated in hypertensive, but not HFpEF, animals. In the kidney, A 1 and A 2A receptor expression showed region-specific, time-dependent changes. In human endothelial cells, A 2A activation or ADA inhibition suppressed endothelin-1-induced COL1, COL3, and TGF-β1 expression, whereas A 2B had no effect. Both A 2A and A 2B restored MnSOD expression, while NOX4 was selectively increased by A 2B . Only A 2A activation induced CAT expression, highlighting its stronger antioxidant role. Conclusion Impaired adenosine metabolism and transport, along with altered receptor signaling contribute to HFpEF progression. Selective A 2A activation attenuates endothelial pro-fibrotic profiles and restores antioxidant defenses, supporting its therapeutic potential. Renal receptor changes reinforce maladaptive cardio-renal crosstalk, emphasizing the importance of multi-organ adenosine modulation in HFpEF and encouraging further translational studies.
Riemma et al. (Wed,) conducted a other in Male Dahl salt-sensitive rats (7 weeks old) with high-salt diet-induced hypertension and heart failure with preserved ejection fraction (HFpEF) phenotype (n=18). High-salt diet (8% NaCl) vs. Low-salt diet (0.3% NaCl) was evaluated on Development of HFpEF characterized by cardiac diastolic dysfunction and structural changes, assessed by echocardiographic and hemodynamic parameters (p=p<0.05 to p<0.0001 reported for differences in individual parameters vs controls). High-salt diet in Dahl rats induced HFpEF evidenced by ~0.7-fold decrease in E/A ratio, ~1.3-fold increase in E deceleration time and IVRT, ~2.5-fold increase in LV end-diastolic pressure, and ~1.3-fold increase in cardiac fibrosis compared to low-salt controls.