{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:21:30Z","timestamp":1787016090444,"version":"build-2736575974"},"reference-count":32,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2017,10,11]],"date-time":"2017-10-11T00:00:00Z","timestamp":1507680000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1140275"],"award-info":[{"award-number":["1140275"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["F32\u2010HL108592\u201001A1"],"award-info":[{"award-number":["F32\u2010HL108592\u201001A1"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["PO1\u2010HL62222"],"award-info":[{"award-number":["PO1\u2010HL62222"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2018,8]]},"abstract":"\n Key points<\/jats:title>\n \n \n \n Enhanced carotid body chemoreflex activity contributes to development of disordered breathing patterns, autonomic dysregulation and increases in incidence of arrhythmia in animal models of reduced ejection fraction heart failure.<\/jats:p>\n <\/jats:list-item>\n \n Chronic reductions in carotid artery blood flow are associated with increased carotid body chemoreceptor activity.<\/jats:p>\n <\/jats:list-item>\n \n Kr\u00fcppel\u2010like Factor 2 (KLF2) is a shear stress\u2010sensitive transcription factor that regulates the expression of enzymes which have previously been shown to play a role in increased chemoreflex sensitivity.<\/jats:p>\n <\/jats:list-item>\n \n We investigated the impact of restoring carotid body KLF2 expression on chemoreflex control of ventilation, sympathetic nerve activity, cardiac sympatho\u2010vagal balance and arrhythmia incidence in an animal model of heart failure.<\/jats:p>\n <\/jats:list-item>\n \n The results indicate that restoring carotid body KLF2 in chronic heart failure reduces sympathetic nerve activity and arrhythmia incidence, and improves cardiac sympatho\u2010vagal balance and breathing stability. Therapeutic approaches that increase KLF2 in the carotid bodies may be efficacious in the treatment of respiratory and autonomic dysfunction in heart failure.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Abstract<\/jats:title>\n \n Oscillatory breathing and increased sympathetic nerve activity (SNA) are associated with increased arrhythmia incidence and contribute to mortality in chronic heart failure (CHF). Increased carotid body chemoreflex (CBC) sensitivity plays a role in this process and can be precipitated by chronic blood flow reduction. We hypothesized that downregulation of a shear stress\u2010sensitive transcription factor, Kr\u00fcppel\u2010like Factor 2 (KLF2), mediates increased CBC sensitivity in CHF and contributes to associated autonomic, respiratory and cardiac sequelae. Ventilation (Ve), renal SNA (RSNA) and ECG were measured at rest and during CBC activation in sham and CHF rabbits. Oscillatory breathing was quantified as the apnoea\u2013hypopnoea index (AHI) and respiratory rate variability index (RRVI). AHI (control 6\u00a0\u00b1\u00a01\/h, CHF 25\u00a0\u00b1\u00a01\/h), RRVI (control 9\u00a0\u00b1\u00a03\/h, CHF 29\u00a0\u00b1\u00a03\/h), RSNA (control 22\u00a0\u00b1\u00a02% max, CHF 43\u00a0\u00b1\u00a05% max) and arrhythmia incidence (control 50\u00a0\u00b1\u00a010\/h, CHF 300\u00a0\u00b1\u00a0100\/h) were increased in CHF at rest (\n \n 21%), as were CBC responses (Ve, RSNA) to 10%\n \n (all\n P<\/jats:italic>\n \u00a0<\u00a00.05\u00a0\n vs<\/jats:italic>\n . control).\n In vivo<\/jats:italic>\n adenoviral transfection of KLF2 to the carotid bodies in CHF rabbits restored KLF2 expression, and reduced AHI (7\u00a0\u00b1\u00a02\/h), RSNA (18\u00a0\u00b1\u00a02% max) and arrhythmia incidence (46\u00a0\u00b1\u00a013\/h) as well as CBC responses to hypoxia (all\n P<\/jats:italic>\n \u00a0<\u00a00.05\n vs<\/jats:italic>\n . CHF empty virus). Conversely, lentiviral KLF2 siRNA in the carotid body decreased KLF2 expression, increased chemoreflex sensitivity, and increased AHI (6\u00a0\u00b1\u00a02\/h\n vs<\/jats:italic>\n . 14\u00a0\u00b1\u00a03\/h), RRVI (5\u00a0\u00b1\u00a03\/h\n vs<\/jats:italic>\n . 20\u00a0\u00b1\u00a03\/h) and RSNA (24\u00a0\u00b1\u00a04% max\n vs<\/jats:italic>\n . 34\u00a0\u00b1\u00a05% max) relative to scrambled\u2010siRNA rabbits. In conclusion, down\u2010regulation of KLF2 in the carotid body increases CBC sensitivity, oscillatory breathing, RSNA and arrhythmia incidence during CHF.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp273805","type":"journal-article","created":{"date-parts":[[2017,10,11]],"date-time":"2017-10-11T16:12:34Z","timestamp":1507738354000},"page":"3171-3185","source":"Crossref","is-referenced-by-count":31,"title":["KLF2 mediates enhanced chemoreflex sensitivity, disordered breathing and autonomic dysregulation in heart failure"],"prefix":"10.1113","volume":"596","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0362-0662","authenticated-orcid":false,"given":"Noah J.","family":"Marcus","sequence":"first","affiliation":[{"name":"Department of Cellular and Integrative Physiology University of Nebraska Medical Center Omaha NE USA"},{"name":"Department of Physiology and Pharmacology Des Moines University Des Moines IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2562-806X","authenticated-orcid":false,"given":"Rodrigo","family":"Del Rio","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology University of Nebraska Medical Center Omaha NE USA"},{"name":"Laboratory of Cardiorespiratory Control Universidad Aut\u00f3noma de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfeng","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology University of Nebraska Medical Center Omaha NE USA"},{"name":"University of North Texas Health Sciences Center Fort Worth TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold D.","family":"Schultz","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology University of Nebraska Medical Center Omaha NE 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