Stephanie L Samani, Shayne C Barlow, Lisa A Freeburg, Grayson M Catherwood, Amelia M Churillo, Traci L Jones, Diego Altomare, Hao Ji, Michael Shtutman, Michael R Zile, Tarek Shazly, Francis G Spinale
{"title":"保留射血分数的猪心力衰竭会导致转录后检查点发生变化。","authors":"Stephanie L Samani, Shayne C Barlow, Lisa A Freeburg, Grayson M Catherwood, Amelia M Churillo, Traci L Jones, Diego Altomare, Hao Ji, Michael Shtutman, Michael R Zile, Tarek Shazly, Francis G Spinale","doi":"10.1152/ajpheart.00551.2023","DOIUrl":null,"url":null,"abstract":"<p><p>Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV <i>K</i><sub>c</sub>) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus will alter posttranscriptional regulation, specifically microRNAs (miRs). LVPO was induced in pigs (<i>n</i> = 9) by sequential ascending aortic cuff and age- and weight-matched pigs (<i>n</i> = 6) served as controls. LV function was measured by echocardiography and LV <i>K</i><sub>c</sub> by speckle tracking. LV myocardial miRs were quantified using an 84-miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed (<i>n</i> = 10, <i>n</i> = 9, respectively). LV samples from LVPO and controls (<i>n</i> = 6, respectively) were subjected to RNA sequencing. LV mass and <i>K</i><sub>c</sub> increased by over 40% with LVPO (<i>P</i> < 0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV <i>K</i><sub>c</sub> (<i>P</i> < 0.05) that mapped to functional domains relevant to <i>K</i><sub>c</sub> such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by fourfold (<i>P</i> < 0.05). RNA analysis identified several genes that mapped to specific miRs that were altered with LVPO. In conclusion, a specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties, and several miRs mapped to molecular pathways that may hold relevance in terms of prognosis and therapeutic targets.<b>NEW & NOTEWORTHY</b> Heart failure with preserved ejection fraction (HFpEF) is an ever-growing cause for the HF burden. HFpEF is particularly difficult to treat as the mechanisms responsible for this specific form of HF are poorly understood. Using a relevant large animal model, this study uncovered a unique molecular signature with the development of HFpEF that regulates specific biological pathways relevant to the progression of this ever-growing cause of HF.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1272-H1285"},"PeriodicalIF":4.1000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560071/pdf/","citationCount":"0","resultStr":"{\"title\":\"Heart failure with preserved ejection fraction in pigs causes shifts in posttranscriptional checkpoints.\",\"authors\":\"Stephanie L Samani, Shayne C Barlow, Lisa A Freeburg, Grayson M Catherwood, Amelia M Churillo, Traci L Jones, Diego Altomare, Hao Ji, Michael Shtutman, Michael R Zile, Tarek Shazly, Francis G Spinale\",\"doi\":\"10.1152/ajpheart.00551.2023\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV <i>K</i><sub>c</sub>) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus will alter posttranscriptional regulation, specifically microRNAs (miRs). LVPO was induced in pigs (<i>n</i> = 9) by sequential ascending aortic cuff and age- and weight-matched pigs (<i>n</i> = 6) served as controls. LV function was measured by echocardiography and LV <i>K</i><sub>c</sub> by speckle tracking. LV myocardial miRs were quantified using an 84-miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed (<i>n</i> = 10, <i>n</i> = 9, respectively). LV samples from LVPO and controls (<i>n</i> = 6, respectively) were subjected to RNA sequencing. LV mass and <i>K</i><sub>c</sub> increased by over 40% with LVPO (<i>P</i> < 0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV <i>K</i><sub>c</sub> (<i>P</i> < 0.05) that mapped to functional domains relevant to <i>K</i><sub>c</sub> such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by fourfold (<i>P</i> < 0.05). RNA analysis identified several genes that mapped to specific miRs that were altered with LVPO. In conclusion, a specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties, and several miRs mapped to molecular pathways that may hold relevance in terms of prognosis and therapeutic targets.<b>NEW & NOTEWORTHY</b> Heart failure with preserved ejection fraction (HFpEF) is an ever-growing cause for the HF burden. HFpEF is particularly difficult to treat as the mechanisms responsible for this specific form of HF are poorly understood. Using a relevant large animal model, this study uncovered a unique molecular signature with the development of HFpEF that regulates specific biological pathways relevant to the progression of this ever-growing cause of HF.</p>\",\"PeriodicalId\":7692,\"journal\":{\"name\":\"American journal of physiology. Heart and circulatory physiology\",\"volume\":\" \",\"pages\":\"H1272-H1285\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560071/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of physiology. Heart and circulatory physiology\",\"FirstCategoryId\":\"88\",\"ListUrlMain\":\"https://doi.org/10.1152/ajpheart.00551.2023\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/6 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Heart and circulatory physiology","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1152/ajpheart.00551.2023","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/6 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
Heart failure with preserved ejection fraction in pigs causes shifts in posttranscriptional checkpoints.
Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV Kc) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus will alter posttranscriptional regulation, specifically microRNAs (miRs). LVPO was induced in pigs (n = 9) by sequential ascending aortic cuff and age- and weight-matched pigs (n = 6) served as controls. LV function was measured by echocardiography and LV Kc by speckle tracking. LV myocardial miRs were quantified using an 84-miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed (n = 10, n = 9, respectively). LV samples from LVPO and controls (n = 6, respectively) were subjected to RNA sequencing. LV mass and Kc increased by over 40% with LVPO (P < 0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV Kc (P < 0.05) that mapped to functional domains relevant to Kc such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by fourfold (P < 0.05). RNA analysis identified several genes that mapped to specific miRs that were altered with LVPO. In conclusion, a specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties, and several miRs mapped to molecular pathways that may hold relevance in terms of prognosis and therapeutic targets.NEW & NOTEWORTHY Heart failure with preserved ejection fraction (HFpEF) is an ever-growing cause for the HF burden. HFpEF is particularly difficult to treat as the mechanisms responsible for this specific form of HF are poorly understood. Using a relevant large animal model, this study uncovered a unique molecular signature with the development of HFpEF that regulates specific biological pathways relevant to the progression of this ever-growing cause of HF.
期刊介绍：
The American Journal of Physiology-Heart and Circulatory Physiology publishes original investigations, reviews and perspectives on the physiology of the heart, vasculature, and lymphatics. These articles include experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the intact and integrative animal and organ function to the cellular, subcellular, and molecular levels. The journal embraces new descriptions of these functions and their control systems, as well as their basis in biochemistry, biophysics, genetics, and cell biology. Preference is given to research that provides significant new mechanistic physiological insights that determine the performance of the normal and abnormal heart and circulation.
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