{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:43:59Z","timestamp":1792622639638,"version":"4.5.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T00:00:00Z","timestamp":1716768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017964","name":"Tianjin Municipal Health Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017964","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Heart failure with preserved ejection fraction (HFpEF) is a multifaceted pathogenesis disease and the exact mechanisms driving HFpEF have not been completely elucidated. Pressure overload hypertrophy (POH) related fibroblasts and M2 macrophages in HFpEF myocardium have been recently identified and are now of great interest. Sympathetic overdrive has also been implicated in HFpEF. This study is designed to dynamically observe the potential roles of aforementioned mechanisms in pathological remodeling and cardiac dysfunction in chronic PO rats. Surgical constriction of the abdominal aorta was used for induction of HFpEF. Echocardiography, electrocardiogram, hemodynamic measurement, hematoxylin and eosin staining, Masson staining, immunohistochemistry and immunofluorescence were performed to assess the changes in heart dysfunction, cardiac remodeling and driving mechanisms at different time points (2, 18, 24\u00a0weeks). The PO induced HFpEF model was well established, which was confirmed by the persistent increase in carotid artery systolic and diastolic blood pressure, and left ventricle hypertrophy at the corresponding postoperative stage. Meanwhile, PO hypertrophy gradually developed into HFpEF, associated with QT and QTc intervals prolongation, normal systolic (EF was maintained at &amp;gt;50%) but impaired diastolic function (increasing LVEDP and LV -dP\/dt<jats:sub>min<\/jats:sub>, abnormal E\/A ratio), increased myocytes size, and observed relatively slight inflammatory infiltration but robust reactive fibrosis. IHC staining further confirmed that macrophages (CD68) but not neutrophils (MPO) or T cells (CD3) accounted for a predominant proportion of infiltrating cells. Mechanistically, we found that the infiltrating macrophages in the heart expressed high levels of CD206 which was simultaneously adjacent to POH fibroblasts appeared to overexpression of \u03b1-SMA in PO rats at late stages. Interestingly, we distinguished two different POHF sub-populations during PO induced HFpEF development, according to non overlapping signals of \u03b1-SMA and PDGFR\u03b1\/\u03b2 proteins. Additionally, PO led to a pronounced exaggeration in sympathetic fibers at all time points. These findings suggest that the establishing model here begins with cardiac sympathetic overdrive, subsequently along with immune cells especially M2 macrophage accumulation and fibroblast heterogeneity at later stages is associated with the development of cardiac maladaptive remodeling and diastolic dysfunction thus further progression to HFpEF.<\/jats:p>","DOI":"10.3389\/fphar.2024.1364758","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T04:13:58Z","timestamp":1716783238000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Cardiac sympathetic overdrive, M2 macrophage activation and fibroblast heterogeneity are associated with cardiac remodeling in a chronic pressure overload rat model of HFpEF"],"prefix":"10.3389","volume":"15","author":[{"given":"Fengjiao","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxue","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1161\/HYPERTENSIONAHA.111.186833","article-title":"Autonomic neural regulation of the immune system: implications for hypertension and cardiovascular disease","volume":"59","author":"Abboud","year":"2012","journal-title":"Hypertens. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.cjca.2020.12.006","article-title":"Cardiovascular autonomic disturbances in heart failure with preserved ejection fraction","volume":"37","author":"Badrov","year":"2021","journal-title":"Can. J. Cardiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/j.yjmcc.2005.02.012","article-title":"A comparative serial echocardiographic analysis of cardiac structure and function in rats subjected to pressure or volume overload","volume":"38","author":"Cantor","year":"2005","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1016\/j.molmed.2019.01.002","article-title":"Macrophages in heart failure with reduced versus preserved ejection fraction","volume":"25","author":"DeBerge","year":"2019","journal-title":"Trends Mol. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"549","DOI":"10.11909\/j.issn.1671-5411.2021.07.009","article-title":"Aging is associated with cardiac autonomic nerve fiber depletion and reduced cardiac and circulating BDNF levels","volume":"18","author":"Elia","year":"2021","journal-title":"J. Geriatr. Cardiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1007\/s00395-013-0357-x","article-title":"Contributions of cardiomyocyte-cardiac fibroblast-immune cell interactions in heart failure development","volume":"108","author":"Fujiu","year":"2013","journal-title":"Basic Res. Cardiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.cardfail.2014.11.004","article-title":"Exaggerated inflammation and monocytosis associate with diastolic dysfunction in heart failure with preserved ejection fraction: evidence of M2 macrophage activation in disease pathogenesis","volume":"21","author":"Glezeva","year":"2015","journal-title":"J. Card. Fail."},{"key":"B8","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1161\/CIRCULATIONAHA.116.022304","article-title":"Leukocyte-expressed \u03b22-adrenergic receptors are essential for survival after acute myocardial injury","volume":"134","author":"Grisanti","year":"2016","journal-title":"Circulation"},{"key":"B9","doi-asserted-by":"publisher","first-page":"809885","DOI":"10.3389\/fcvm.2021.809885","article-title":"A preclinical rat model of heart failure with preserved ejection fraction with multiple comorbidities","volume":"8","author":"Hubesch","year":"2022","journal-title":"Front. Cardiovasc. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1084\/jem.20171274","article-title":"Cardiac macrophages promote diastolic dysfunction","volume":"215","author":"Hulsmans","year":"2018","journal-title":"J. Exp. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"H330","DOI":"10.1152\/ajpheart.00054.2019","article-title":"Platelet-derived growth factor receptor-\u03b1 is essential for cardiac fibroblast survival","volume":"317","author":"Ivey","year":"2019","journal-title":"Am. J. Physiol. - Hear. Circ. Physiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1161\/01.CIR.0000020689.12472.E0","article-title":"Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats","volume":"106","author":"Kuwahara","year":"2002","journal-title":"Circulation"},{"key":"B13","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1161\/01.HYP.0000118584.33350.7d","article-title":"Hypertensive myocardial fibrosis and diastolic dysfunction: another model of inflammation?","volume":"43","author":"Kuwahara","year":"2004","journal-title":"Hypertension"},{"key":"B14","doi-asserted-by":"publisher","first-page":"H443","DOI":"10.1152\/ajpheart.00594.2022","article-title":"Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype","volume":"324","author":"Li","year":"2023","journal-title":"Am. J. Physiol. - Hear. Circ. Physiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1804","DOI":"10.1161\/CIRCRESAHA.114.302524","article-title":"The autonomic nervous system and hypertension","volume":"114","author":"Mancia","year":"2014","journal-title":"Circ. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e13453","DOI":"10.1111\/acel.13453","article-title":"Chronic low-grade inflammation in heart failure with preserved ejection fraction","volume":"20","author":"Mesquita","year":"2021","journal-title":"Aging Cell"},{"key":"B17","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1007\/s00109-015-1314-y","article-title":"Cardiac fibroblasts: from development to heart failure","volume":"93","author":"Moore-Morris","year":"2015","journal-title":"J. Mol. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1038\/s41569-019-0286-y","article-title":"Heart failure as interstitial cancer: emergence of a malignant fibroblast phenotype","volume":"17","author":"Oatmen","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"173","DOI":"10.5935\/abc.20180248","article-title":"The effects of trimetazidine on QT-interval prolongation and cardiac hypertrophy in diabetic rats","volume":"112","author":"Ramezani-Aliakbari","year":"2019","journal-title":"Arq. Bras. Cardiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.yjmcc.2017.10.006","article-title":"Echocardiographic evaluation of diastolic function in mouse models of heart disease","volume":"114","author":"Schnelle","year":"2018","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"242","DOI":"10.3390\/cells9010242","article-title":"Cellular and molecular differences between HFpEF and HFrEF: a step ahead in an improved pathological understanding","volume":"9","author":"Simmonds","year":"2020","journal-title":"Cells"},{"key":"B22","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.jep.2019.02.011","article-title":"PKA\/\u03b22-AR-Gs\/Gi signaling pathway is associated with anti-inflammatory and pro-apoptotic effects of Fuzi and Banxia combination on rats subjected to pressure overload","volume":"235","author":"Sun","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"2493","DOI":"10.3892\/ijmm.2018.3449","article-title":"Stage\u2011dependent changes of \u03b22\u2011adrenergic receptor signaling in right ventricular remodeling in monocrotaline\u2011induced pulmonary arterial hypertension","volume":"41","author":"Sun","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/s1674-6384(14)60044-7","article-title":"Protection of shengmai recipe on improving cardiac function and attenuating kidney injury in pressure overload rats","volume":"6","author":"Sun","year":"2014","journal-title":"Chin. Herb. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"677727","DOI":"10.3389\/fcvm.2021.677727","article-title":"A porcine model of heart failure with preserved ejection fraction induced by chronic pressure overload characterized by cardiac fibrosis and remodeling","volume":"8","author":"Tan","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e003989","DOI":"10.1161\/JAHA.116.003989","article-title":"Biomarker profiles in heart failure patients with preserved and reduced ejection fraction","volume":"6","author":"Tromp","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"B27","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1007\/s11906-018-0893-8","article-title":"Modulation of sympathetic overactivity to treat resistant hypertension","volume":"20","author":"Voora","year":"2018","journal-title":"Curr. Hypertens. Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1161\/CIRCHEARTFAILURE.109.931451","article-title":"Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction","volume":"4","author":"Westermann","year":"2011","journal-title":"Circ. Hear. Fail."},{"key":"B29","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/1475-2840-6-14","article-title":"Noninvasive and invasive evaluation of cardiac dysfunction in experimental diabetes in rodents","volume":"6","author":"Wichi","year":"2007","journal-title":"Cardiovasc. Diabetol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"3892","DOI":"10.1158\/0008-5472.CAN-19-2691","article-title":"Interaction with CD68 and regulation of GAS6 expression by endosialin in fibroblasts drives recruitment and polarization of macrophages in hepatocellular carcinoma","volume":"80","author":"Yang","year":"2020","journal-title":"Cancer Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"646240","DOI":"10.3389\/fphar.2021.646240","article-title":"Resveratrol ameliorates cardiac remodeling in a murine model of heart failure with preserved ejection fraction","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.7150\/IJBS.65802","article-title":"CXCR4-dependent macrophage-to-fibroblast signaling contributes to cardiac diastolic dysfunction in heart failure with preserved ejection fraction","volume":"18","author":"Zhang","year":"2022","journal-title":"Int. J. Biol. Sci."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1364758\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T04:14:02Z","timestamp":1716783242000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1364758\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,27]]},"references-count":32,"alternative-id":["10.3389\/fphar.2024.1364758"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1364758","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,27]]},"article-number":"1364758"}}