This study states that Many patients with heart failure with preserved ejection fraction (HFpEF) have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with HFpEF portend a poor prognosis; this phenotype is referred to as combined pre-and post-capillary PH (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery smooth muscle cells (PAVSMCs).

We used obese ZSF-1 leptin-receptor knock-out rats (HFpEF model), obese ZSF-1 rats treated with SU5416 to stimulate resting PH (Obese+sugen, CpcPH model), and Lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated via implanted-catheters during treadmill exercise. PA function was evaluated using MRI and myography. Overexpression of NFYA, a transcriptional-enhancer of sGCβ1, was performed by PA delivery of adeno-associated-virus 6 (AAV6). Treatment groups received SGLT2 inhibitor Empagliflozin in drinking water. PAVSMCs from rats and humans were cultured with Palmitic acid, Glucose, and Insulin (PGI) to induce metabolic-stress.

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