Internal Medicine Commons^™

Interplay Of Hypoxia-Inducible Factors And Oxygen Therapy In Cardiovascular Medicine, Yafen Liang, Wei Ruan, Yandong Jiang, Richard Smalling, Xiaoyi Yuan, Holger K Eltzschig

Journal Articles

Mammals have evolved to adapt to differences in oxygen availability. Although systemic oxygen homeostasis relies on respiratory and circulatory responses, cellular adaptation to hypoxia involves the transcription factor hypoxia-inducible factor (HIF). Given that many cardiovascular diseases involve some degree of systemic or local tissue hypoxia, oxygen therapy has been used liberally over many decades for the treatment of cardiovascular disorders. However, preclinical research has revealed the detrimental effects of excessive use of oxygen therapy, including the generation of toxic oxygen radicals or attenuation of endogenous protection by HIFs. In addition, investigators in clinical trials conducted in the past decade have …

Prolylcarboxypeptidase Alleviates Hypertensive Cardiac Remodeling By Regulating Myocardial Tissue Angiotensin Ii, Binh Y Nguyen, Fangchao Zhou, Pablo Binder, Wei Liu, Susanne S Hille, Xiaojing Luo, Min Zi, Hongyuan Zhang, Antony Adamson, Fozia Z Ahmed, Sam Butterworth, Elizabeth J Cartwright, Oliver J Müller, Kaomei Guan, Elizabeth M Fitzgerald, Xin Wang

Journal Articles

Background Prolonged activation of angiotensin II is the main mediator that contributes to the development of heart diseases, so converting angiotensin II into angiotensin 1-7 has emerged as a new strategy to attenuate detrimental effects of angiotensin II. Prolylcarboxypeptidase is a lysosomal pro-X carboxypeptidase that is able to cleave angiotensin II at a preferential acidic pH optimum. However, insufficient attention has been given to the cardioprotective functions of prolylcarboxylpeptidase. Methods and Results We established a CRISPR/CRISPR-associated protein 9-mediated global prolylcarboxylpeptidase-knockout and adeno-associated virus serotype 9-mediated cardiac prolylcarboxylpeptidase overexpression mouse models, which were challenged with the angiotensin II infusion (2 mg/kg …

Sirpα Mediates Igf1 Receptor In Cardiomyopathy Induced By Chronic Kidney Disease, Sandhya S Thomas, Jiao Wu, Giovanni Davogustto, Michael W Holliday, Kristin Eckel-Mahan, Daniela Verzola, Giacomo Garibotto, Zhaoyong Hu, William E Mitch, Heinrich Taegtmeyer

Journal Articles

BACKGROUND: Chronic kidney disease (CKD) is characterized by increased myocardial mass despite near-normal blood pressure, suggesting the presence of a separate trigger. A potential driver is SIRPα (signal regulatory protein alpha)-a mediator impairing insulin signaling. The objective of this study is to assess the role of circulating SIRPα in CKD-induced adverse cardiac remodeling.

METHODS: SIRPα expression was evaluated in mouse models and patients with CKD. Specifically, mutant, muscle-specific, or cardiac muscle-specific SIRPα KO (knockout) mice were examined after subtotal nephrectomy. Cardiac function was assessed by echocardiography. Metabolic responses were confirmed in cultured muscle cells or cardiomyocytes.

RESULTS: We demonstrate that …

Prolonged Cardiac Nr4a2 Activation Causes Dilated Cardiomyopathy In Mice, Sadia Ashraf, Heinrich Taegtmeyer, Romain Harmancey

Journal Articles

Transcription factors play a fundamental role in cardiovascular adaptation to stress. Nuclear receptor subfamily 4 group A member 2 (NR4A2; NURR1) is an immediate-early gene and transcription factor with a versatile role throughout many organs. In the adult mammalian heart, and particularly in cardiac myocytes, NR4A2 is strongly up-regulated in response to beta-adrenergic stimulation. The physiologic implications of this increase remain unknown. In this study, we aimed to interrogate the consequences of cardiac NR4A2 up-regulation under normal conditions and in response to pressure overload. In mice, tamoxifen-dependent, cardiomyocyte-restricted overexpression of NR4A2 led to cardiomyocyte hypertrophy, left ventricular dilation, heart failure, …

Guidelines On Models Of Diabetic Heart Disease, Lisa C Heather, Anne D Hafstad, Ganesh V Halade, Romain Harmancey, Kimberley M Mellor, Paras K Mishra, Erin E Mulvihill, Miranda Nabben, Michinari Nakamura, Oliver J Rider, Matthieu Ruiz, Adam R Wende, John R Ussher

Journal Articles

Diabetes is a major risk factor for cardiovascular diseases, including diabetic cardiomyopathy, atherosclerosis, myocardial infarction, and heart failure. As cardiovascular disease represents the number one cause of death in people with diabetes, there has been a major emphasis on understanding the mechanisms by which diabetes promotes cardiovascular disease, and how antidiabetic therapies impact diabetic heart disease. With a wide array of models to study diabetes (both type 1 and type 2), the field has made major progress in answering these questions. However, each model has its own inherent limitations. Therefore, the purpose of this guidelines document is to provide the …

Ucp3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin Ii-Induced Hypertension, Xu Chen, Sadia Ashraf, Nadia Ashraf, Romain Harmancey

Journal Articles

Background Left ventricular diastolic dysfunction, an early stage in the pathogenesis of heart failure with preserved ejection fraction, is exacerbated by joint exposure to hypertension and obesity; however, the molecular mechanisms involved remain uncertain. The mitochondrial UCP3 (uncoupling protein 3) is downregulated in the heart with obesity. Here, we used a rat model of UCP3 haploinsufficiency (ucp3

Ucp3 (Uncoupling Protein 3) Insufficiency Exacerbates Left Ventricular Diastolic Dysfunction During Angiotensin Ii-Induced Hypertension, Xu Chen, Sadia Ashraf, Nadia Ashraf, Romain Harmancey

Journal Articles

Background Left ventricular diastolic dysfunction, an early stage in the pathogenesis of heart failure with preserved ejection fraction, is exacerbated by joint exposure to hypertension and obesity; however, the molecular mechanisms involved remain uncertain. The mitochondrial UCP3 (uncoupling protein 3) is downregulated in the heart with obesity. Here, we used a rat model of UCP3 haploinsufficiency (ucp3

Dietary Fat And Sugar Differentially Affect Β-Adrenergic Stimulation Of Cardiac Erk And Akt Pathways In C57bl/6 Male Mice Subjected To High-Calorie Feeding, Sadia Ashraf, Gizem Yilmaz, Xu Chen, Romain Harmancey

Journal Articles

BACKGROUND: High dietary fat and sugar promote cardiac hypertrophy independently from an increase in blood pressure. The respective contribution that each macronutrient exerts on cardiac growth signaling pathways remains unclear.

OBJECTIVE: The goal of this study was to investigate the mechanisms by which high amounts of dietary fat and sugar affect cardiac growth regulatory pathways.

METHODS: Male C57BL/6 mice (9 wk old; n = 20/group) were fed a standard rodent diet (STD; kcal% protein-fat-carbohydrate, 29-17-54), a high-fat diet (HFD; 20-60-20), a high-fat and high-sugar Western diet (WD; 20-45-35), a high-sugar diet with mixed carbohydrates (HCD; 20-10-70), or a high-sucrose diet …

Nuclear Receptor Subfamily 4 Group A Member 2 Inhibits Activation Of Erk Signaling And Cell Growth In Response To Β-Adrenergic Stimulation In Adult Rat Cardiomyocytes, Sadia Ashraf, Yassmin K Hegazy, Romain Harmancey

Journal Articles

Sustained elevation of sympathetic activity is an important contributor to pathological cardiac hypertrophy, ventricular arrhythmias, and left ventricular contractile dysfunction in chronic heart failure. The orphan nuclear receptor NR4A2 is an immediate early-response gene activated in the heart under β-adrenergic stimulation. The goal of this study was to identify the transcriptional remodeling events induced by increased NR4A2 expression in cardiomyocytes and their impact on the physiological response of those cells to sustained β-adrenergic stimulation. Treatment of adult rat ventricular myocytes with isoproterenol induced a rapid (<4 >h) increase in NR4A2 levels that was accompanied by a transient (<24 >h) increase …