Hypertension; Diastolic Function; Diabetes; Heart Failure; Oxidative Stress; NOX
Mochizuki Michika, Lorenz Vera, Ivanek Robert, Della Verde Giacomo, Gaudiello Emanuele, Marsano Anna, Pfister Otmar, Kuster Gabriela M (2017), Polo-Like Kinase 2 is Dynamically Regulated to Coordinate Proliferation and Early Lineage Specification Downstream of Yes-Associated Protein 1 in Cardiac Progenitor Cells., in Journal of the American Heart Association
, 6(10), e005920.
Steinl David C, Xu Lifen, Khanicheh Elham, Ellertsdottir Elin, Ochoa-Espinosa Amanda, Mitterhuber Martina, Glatz Katharina, Kuster Gabriela M, Kaufmann Beat A (2016), Noninvasive Contrast-Enhanced Ultrasound Molecular Imaging Detects Myocardial Inflammatory Response in Autoimmune Myocarditis., in Circulation. Cardiovascular imaging
, 9(8), e004720.
Khanicheh Elham, Qi Yue, Xie Aris, Mitterhuber Martina, Xu Lifen, Mochizuki Michika, Daali Youssef, Jaquet Vincent, Krause Karl-Heinz, Ruggeri Zaverio M, Kuster Gabriela M, Lindner Jonathan R, Kaufmann Beat A (2013), Molecular imaging reveals rapid reduction of endothelial activation in early atherosclerosis with apocynin independent of antioxidative properties., in Arteriosclerosis, thrombosis, and vascular biology
, 33(9), 2187-92.
Heart failure (HF) with preserved ejection fraction (EF) (HFPEF) has emerged as a distinct disease entity that accounts for roughly half of all HF cases. Diagnostic criteria of HFPEF include clinical signs or symptoms of HF and echocardiographic evidence of normal left ventricular systolic but abnormal diastolic function. Prevalence of hypertension and diabetes is high among patients with HFPEF and both conditions are associated with diastolic dysfunction. Whereas survival improved in patients with HF with reduced EF due to recent advances in therapy, mortality remained high in HFPEF as neurohumoral inhibitors failed to improve outcome in these patients. Understanding of the pathophysiology of HFPEF is still vague and evidence-based guidelines for treatment of diastolic dysfunction and HFPEF are lacking. Potential mechanisms of the left ventricular diastolic dysfunction underlying HFPEF integrate abnormalities of the extracellular matrix, the cardiomyocytes (CMC) and their myofilamentary proteins. Oxidative stress is an important factor in these processes and reactive oxygen species (ROS) originating from NADPH oxidase (NOX) have been implicated in myocardial fibrosis, hypertrophy and impaired calcium handling associated with diastolic dysfunction. NOX are transmembrane proteins dedicated to the production of ROS and NOX2, 4 as well as recently NOX1 have been identified in the heart. Whereas NOX2 and 4 contribute to cardiac hypertrophy and fibrosis, NOX1 has been implicated in blood pressure regulation and vascular remodeling. However, the role of NOX1 in cardiac remodeling has not been investigated. Preliminary data from our laboratory demonstrate significant regulation of NOX1 in CMC in response to high glucose (HG) and neurohormonal stimulation, as well as marked contribution of NOX1 to HG-induced NOX activity and CMC apoptosis, prompting us to hypothesize that NOX1 is involved in cardiac remodeling in metabolic and hypertensive heart disease (HHD), which are both associated with diastolic dysfunction/failure. Therefore, the overall goal of this study is to define the role of NOX1 in the pathophysiology of diastolic dysfunction and HFPEF. Specific Aim 1. To test the hypothesis that NOX1 contributes to cardiac remodeling in HHD associated with diastolic dysfunction and HFPEF. Mice will be inserted micro-osmotic minipumps for s.c. release of angiotensin II for up to four weeks and the role of NOX1 will be examined using NOX1-/y mice, myocardial shRNA injection and pharmacological inhibition. Cardiac morphology and function will be assessed by echocardiography as well as immunohistochemistry and molecular tissue analyses at the time of termination.Specific Aim 2. To test the hypothesis that NOX1 contributes to metabolic/type II diabetic cardiac remodeling associated with diastolic dysfunction and HFPEF in a mouse model of western diet. NOX1-/y and wt mice will be fed a high fat/high sugar diet to induce metabolic syndrome/type II diabetes. After eight months, cardiac morphology and function will be assessed as outlined above. Specific Aim 3. To define NOX regulation and identify the molecular mechanisms underlying NOX- mediated hypertrophic and hyperglycemic CMC remodeling in vitro. Complementary in vitro experiments will be performed in normal and siRNA-mediated NOX1-, 2- or 4-silenced rat CMC to assess and identify mechanisms of regulated NOX expression and NOX-isoform-dependent signaling in hypertrophic and hyperglycemic CMC remodeling.Significance and Outlook: NOX-derived ROS have been shown to mediate important features relevant to diastolic dysfunction and HFPEF. Improved pathophysiological understanding of HFPEF and of the roles of different NOX isoforms is mandatory to develop novel therapeutic strategies that may consist of the isoform-specific inhibition of NOX for prevention and treatment of HFPEF in the future.