Heart failure, the clinical syndrome of end-stage cardiac disease of diverse etiologies, is a major cause of morbidity and mortality. Indeed, the incidence and prevalence of heart failure in affluent societies are increasing due to demographics with rising proportion of elderly, as well as increased survival of myocardial infarction. Despite implementation of several new treatment modalities during the last 20 years, heart failure is still a progressive and ominous condition indicating that important pathogenic mechanisms remain unmodified by the most current treatment modalities. Thus, there is an impetus for new and more effective pharmacological interventions.
In evolving heart failure, multiple compensatory actions are triggered in order to maintain cardiac output, among which is activation of the sympathetic nervous system, the renin-angiotensin system, as well as a number of autocrine/paracrine factors synthesized in myocardial tissue. These compensatory actions also reflect in alterations of cardiac structure, collectively called cardiac remodeling. The most important structural alterations are cardiac myocyte hypertrophy and myocardial fibrosis. Although cardiac remodeling may initially balance loss of contractile force, the continuum of these structural alterations often feeds into vicious circles leading to progression of cardiac dysfunction. Despite substantial new insights into the mechanisms of myocardial hypertrophy and fibrosis, many of the nodal points that orchestrate these structural alterations still remain to be identified. Thus, an important focus of our research group is to unravel the signal transduction mechanisms that generate the dysfunctional signals leading to pathologic remodeling and progression of heart failure. Another important conceptual approach is that of delineating mechanisms that either increases or decreases the tolerance of cardiac myocytes to hypoxia or free oxygen radical injury, i.e. potential mediators of cardiac myocyte damage in evolving heart failure. The purpose of these investigations is to provide new knowledge of disease mechanisms, enabling development of novel pharmacological interventions for heart failure.
Our research group is a multidisciplinary team of experts in gene technology, molecular and cellular biology, as well as experimental and clinical medicine. The research efforts comprise studies of isolated cardiac myocytes and fibroblasts, integrated physiology in genetically engineered mice, large animal studies, as well as clinical investigations. Our research group is member of the Center for Heart Failure Research, University of Oslo (www.heartfailure.no), a thematic research initiative and focus area of research selected by the Faculty of Medicine. The Center for Heart Failure Research is also a regional research network sponsored by the Regional Health Authority Helse Sør-Øst. The Institute for Surgical Research provides infrastructure with state-of-the-art equipment for gene technology, as well as for high-resolution echocardiography and integrated physiologic assessment of cardiac function in both small and large animals.
Dysfunctional cardiac signaling mechanisms and signals astray are considered major causes of pathologic myocardial hypertrophy and predisposition to heart failure. Increasingly, dysfunctional signaling mechanisms are implicated in increased production of free oxygen radicals, mitochondrial dysfunction and reduced tolerance to hypoxia. Thus, a major goal of our research group is to dissect the function of myocardial autocrine/paracrine factors, their cognate receptors, and intracellular pathways in cardiac myocytes and fibroblasts. Of particular interest is also the cross-talk and intracellular signaling between cardiac fibroblasts and cardiac myocytes. New knowledge on the function and mechanisms of signaling pathways in the heart may provide basis for development of new and more effective therapeutic intervention in acute coronary syndromes and heart failure.
Current specific aims of the research group
- Elucidate the function of novel G protein-coupled receptors and their signaling pathways in the heart.
- Resolve how G protein-coupled receptor kinases (GRK) control the sensitivity of receptors to their cognate agonists, as well as decipher the role of GRKs in controlling G protein-dependent versus G protein-independent signaling in the heart in health and disease, with particular focus on heart failure.
- Uncover the function of myocardial autocrine/paracrine factors or cytokines that are activated or induced in heart failure. Current focus is on delineating the target cells and the functions of secreted matricellular CCN proteins, in particular CCN1, CCN2/CTGF (connective tissue growth factor), and CCN5/WISP-2 (Wnt-inducible secreted protein-2), secreted regulators of Wnt signaling, as well as the TGF-ß superfamily cytokine GDF-15 in heart failure. The CCN proteins (CCN is an acronym for the first three members of this gene family; Cyr61, CTGF, Nov) are cysteine-rich, modular proteins considered to interact with various proteins in the extracellular matrix, including cytokines, growth factors, extracellular matrix proteins, as well as receptors on the cell surface. Yet, the mechanisms of CCN protein action are poorly understood. We have established eukaryotic expression systems for production and purification of recombinant CCN1, CCN2, and CCN5 in order to investigate the signaling mechanisms and biologic functions of these proteins in cardiac myocytes and cardiac fibroblasts.
Growth coordination during development
Mar 27, 2017
Jørgen Wesche appointed group leader for the Mesenchymal Cancer Biology Group at the Department of Tumor Biology
Mar 15, 2017
Prestigious research prize from the Norwegian Cancer Society to pioneer in autophagy research
Mar 7, 2017
Palmitate promotes inflammatory responses and cellular senescence in cardiac fibroblasts
Biochim Biophys Acta, 1862 (2), 234-245
CTGF/CCN2 Postconditioning Increases Tolerance of Murine Hearts towards Ischemia-Reperfusion Injury
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NLRP3 inflammasome activation during myocardial ischemia reperfusion is cardioprotective
Biochem Biophys Res Commun, 469 (4), 1012-20