hypertrophy; growth factors; cardiac remodeling; heart failure; signal transduction; G-protein coupled receptors
Xu Lifen, Brink Marijke (2016), mTOR, cardiomyocytes and inflammation in cardiac hypertrophy, in Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
, 1863(7), 1894-1903.
Pentassuglia Laura, Heim Philippe, Lebboukh Sonia, Morandi Christian, Xu Lifen, Brink Marijke (2016), Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes, in American Journal of Physiology-Endocrinology and Metabolism
, 310(9), E782-E794.
Shende Pankaj, Xu Lifen, Morandi Christian, Pentassuglia Laura, Heim Philippe, Lebboukh Sonia, Berthonneche Corinne, Pedrazzini Thierry, Kaufmann Beat A., Hall Michael N., Rüegg Markus A., Brink Marijke (2015), Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy, in Cardiovascular Research
, 109, 103-114.
Shende Pankaj, Plaisance Isabelle, Morandi Christian, Pellieux Corinne, Berthonneche Corinne, Zorzato Francesco, Krishnan Jaya, Lerch René, Hall Michael N, Rüegg Markus A, Pedrazzini Thierry, Brink Marijke (2011), Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice., in Circulation
, 123(10), 1073-82.
Brink Marijke and Nichols Marc (2011), European Perspectives in Cardiology - Spotlight Marijke Brink
, Circulation, LWW (Wolters Kluwer), USA.
The heart is a plastic organ which gradually changes its geometry, cellular composition and function during the development of metabolic and cardiovascular disease, especially hypertension and ischemic heart disease but also independently during obesity and diabetes. Specific cardiac changes are associated with disturbed neurohormonal balances and inflammatory responses and if pathological triggers are not controlled in a timely manner, heart failure may develop. Heart failure is a most pressing health problem and economic burden because it affects high numbers of elderly individuals in our Western society.Relevant to adaptive and maladaptive cardiac growth responses occurring in the above-mentioned pathologies, my laboratory has previously established pathways by which the inflammatory mediator tumor necrosis factor (TNF)-a and the metabolic mediator insulin-like growth factor (IGF)-I regulate protein translation and degradation in myocytes. We demonstrated that IGF-I stimulates protein translation via mammalian target of rapamycin (mTOR) and blocks TNF-a-induced expression of atrogin-1, an enzyme known to target sarcomere proteins for proteasomal degradation and cause atrophy. mTOR occurs in two functionally and structurally distinct protein complexes, mTORC1 and mTORC2, of which the functions in health and during cardiac remodeling are not known. The research proposed here aims to place these two branches of mTOR signaling into heart-specific pathways of atrophy and hypertrophy induced by stimuli such as insulin, IGF-I, TNF-a and phenylephrine. Thus, we will use our recent mechanistic insights to assess how mTOR coordinates protein turnover and energy metabolism via mTORC1 and mTORC2 under baseline conditions and during adaptations of the heart to physiological or pathological stress. To this end, we have developed mouse models from which raptor and rictor, essential components of mTORC1 and mTORC2, are deleted in a temporally-controlled and cardiomyocyte specific manner. Data obtained to date show that cardiac mTORC1 inactivition causes dilated cardiomyopathy within six weeks and that the development of dysfuncion is precipitated under conditions of increased cardiac preload or afterload. We will use these in vivo models in combination with primary cardiomyocyte cultures to analyze the distinct mTOR-mediated cellular mechanisms that affect cardiac function. Our specific aims are:1: to dissect the molecular and cellular pathways in which mTORC1 and mTORC2 are implicated in the heart under baseline conditions.2: to test if mTORC2 inactivation leads to reduced cardiac function via changed metabolism under conditions of cardiac stress.3: to identify compensatory pathways of muscle protein synthesis in sedentary and exercising mice.The better understanding of cardiac growth regulatory pathways that we will obtain with our studies may contribute to a rationale for better prevention as well as to the identification of new therapeutic targets to treat cardiac disease at an early stage. Moreover, since mTOR inhibitors have strong potential as immunosuppressive and anti-cancer drugs, knowledge on the cardiac functions of mTORC1 and mTORC2 is important.