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Selective inhibition of phosphodiesterase 9A (PDE9A) has emerged as a potential therapeutic approach for treating cardiometabolic diseases. Coronary microvascular disease (CMD) is one of the key mechanisms contributing to the development of left ventricular (LV) diastolic dysfunction in HFpEF. Our study aimed to investigate the mechanisms by which PDE9A inhibition could ameliorate CMD and improve LV diastolic function in HFpEF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>The obese diabetic Zucker fatty\/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat model of HFpEF was employed in which it was found that a progressively developing coronary microvascular rarefaction is associated with LV diastolic dysfunction when compared to lean, nondiabetic hypertensive controls. Obese ZSF1 rats had an increased cardiac expression of PDE9A. Treatment of obese ZSF1 rats with the selective PDE9A inhibitor, PF04447943 (3\u2009mg\/kg\/day, oral gavage for 2\u2009weeks), improved coronary microvascular rarefaction and LV diastolic dysfunction, which was accompanied by reduced levels of oxidative and nitrosative stress markers, hydrogen peroxide, and 3\u2010nitrotyrosine. Liquid chromatography\u2013mass spectrometry (LC\u2013MS) proteomic analysis identified peroxiredoxins (PRDX) as downregulated antioxidants in the heart of obese ZSF1 rats, whereas Western immunoblots showed that the protein level of PRDX5 was significantly increased by the PF04447943 treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Thus, in the ZSF1 rat model of human HFpEF, PDE9A inhibition improves coronary vascular rarefaction and LV diastolic dysfunction, demonstrating the usefulness of PDE9A inhibitors in ameliorating CMD and LV diastolic dysfunction through augmenting PRDX\u2010dependent antioxidant mechanisms.<\/jats:p><\/jats:sec>","DOI":"10.1111\/micc.12888","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T17:09:19Z","timestamp":1727370559000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["<scp>PDE9A<\/scp> Inhibition Improves Coronary Microvascular Rarefaction and Left Ventricular Diastolic Dysfunction in the <scp>ZSF1<\/scp> Rat Model of <scp>HFpEF<\/scp>"],"prefix":"10.1111","volume":"31","author":[{"given":"Katie Anne","family":"Fopiano","sequence":"first","affiliation":[{"name":"Department of Physiology, Medical College of Georgia Augusta University  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saltanat","family":"Zhazykbayeva","sequence":"additional","affiliation":[{"name":"Department of Cellular and Translational Physiology, Institute of Physiology Ruhr University Bochum  Bochum Germany"},{"name":"Institut F\u00fcr Forschung Und Lehre (IFL), Molecular and Experimental Cardiology Ruhr University Bochum  Bochum Germany"},{"name":"Department of Cardiology St. Josef\u2010Hospital, UK RUB, Ruhr University Bochum  Bochum Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"El\u2010Battrawy","sequence":"additional","affiliation":[{"name":"Department of Cellular and Translational Physiology, Institute of Physiology Ruhr University Bochum  Bochum Germany"},{"name":"Institut F\u00fcr Forschung Und Lehre (IFL), Molecular and Experimental Cardiology Ruhr University Bochum  Bochum Germany"},{"name":"Department of Cardiology St. Josef\u2010Hospital, UK RUB, Ruhr University Bochum  Bochum Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8582-6957","authenticated-orcid":false,"given":"Vadym","family":"Buncha","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical College of Georgia Augusta University  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"Pearson","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical College of Georgia Augusta University  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davis J.","family":"Hardell","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical College of Georgia Augusta University  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwei","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical College of Georgia Augusta University  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazha","family":"Hamdani","sequence":"additional","affiliation":[{"name":"Department of Cellular and Translational Physiology, Institute of Physiology Ruhr University Bochum  Bochum Germany"},{"name":"Institut F\u00fcr Forschung Und Lehre (IFL), Molecular and Experimental Cardiology Ruhr University Bochum  Bochum Germany"},{"name":"Department of Cardiology St. Josef\u2010Hospital, UK RUB, Ruhr University Bochum  Bochum Germany"},{"name":"Department of Pharmacology and Pharmacotherapy Center for Pharmacology and Drug Research &amp; Development HCEMM\u2010SU Cardiovascular Comorbidities Research Group  Budapest Hungary"},{"name":"Department of Physiology Cardiovascular Research Institute Maastricht University Maastricht  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8755-2980","authenticated-orcid":false,"given":"Zsolt","family":"Bagi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical College of Georgia Augusta University  Augusta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11897-013-0155-7"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.080770"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.313572"},{"key":"e_1_2_9_5_1","first-page":"582","article-title":"Heart Failure With Preserved Ejection Fraction: Diagnosis and Management","volume":"96","author":"Gazewood J. 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