The major research focus is on unraveling key molecular mechanisms in the pathogenesis and progression of heart failure. Our goal is to identify novel targets of intervention and to develop novel pharmacologic therapies based on inventions done in our laboratory. Major efforts are currently aimed at deciphering the role of fibrosis and cellular ageing in development of a form of heart failure often associated with high blood pressure, diabetes and/or obesity (diastolic dysfunction/ heart failure with preserved ejection fraction - HFpEF). This subset of heart failure accounts for nearly 50% of all patients diagnosed with heart failure and responds poorly to current treatment regimens.

The research of projects spans from biochemical structure-activity studies of target proteins, cell biologic studies, to experimental studies in appropriate disease models in genetically engineered mice. Several ongoing studies focus on CCN proteins, a family of matricellular proteins/growth factors that has been shown to be involved in tissue repair mechanisms and fibrosis. We have recently uncovered that these proteins are secreted as preproproteins that requires proteolytic processing following secretion from cells in order to become biologically active (Kaasboll, OJ et al J Biol Chem 293(46):17953-17970, 2018).

Our research group is a multidisciplinary team of medical doctors, biochemists, and molecular biologists. Our team is proficient in a wide range of technologies from proteomics and studies of protein structure-activity relationships, cell biologic studies of isolated primary cells from the heart, and studies of disease models in genetically engineered mice.

The research group has state-of-the-art facilities and equipment for studies of disease models in genetically engineered mice, including high resolution Doppler/echocardiography and molecular imaging of small animals. The research group collaborates with leading international groups and is part of large research community at Oslo University Hospital and University of Oslo focusing on cardiovascular research.


Current research projects

Elucidate the function of the hydroxycarboxylic acid receptor GPR81/HCA1 and its cognate ligand (L-lactate) in the heart under physiologic conditions and evolving heart failure.

We have demonstrated that cardiac myocytes express GPR81 and lactate inhibits synthesis of cAMP in cardiac myocytes via activation of GPR81. We have also shown that cardiac myocyte GPR81 is upregulated in heart failure in proportion to the functional derangement. Currently, we are investigating the role of GPR81 in heart failure using genetically-engineered mice.

Resolve the role of G protein-coupled receptor kinases (GRK) in regulation of G protein-dependent versus G protein-independent (biased) signaling in the heart in health and disease, with particular focus on heart failure.

Previous studies from our laboratory have revealed that GRK2 and GRK3 in cardiac myocytes display striking specificity at G protein-coupled receptors controlling different aspects of cardiac function. Overall, our data have uncovered the novel findings that GRK3 has substantially higher potency and efficacy than GRK2 at endogenous endothelin receptors (ET-R) and a1-adrenergic receptors (1-AR). This did not seem to be the case for the ß1-adrenergic receptor as GRK3 potency at this receptor appeared much weaker than for the ET-R, and was equipotent with GRK2. Thus, GRK3 emerges as a primary regulator of ET-R and of a1- AR-signaling in cardiac myocytes. The distinct receptor specificity of GRK3 may have important implications in cardiac function. These functional differences are currently subject of investigations in transgenic and gene-targeted mice.Another ongoing effort is aimed at resolving the role of GRK5 in regulation of tolerance to ischemia/reperfusion injury as well as in the pathophysiology of heart failure. In a report from our laboratory published in 2013 (Gravning J et al. Mol Pharmacol 84:372-383,2013) we disclosed the novel findings that myocardial GRK5 is upregulated in transgenic mice with cardiac-restricted overexpression of CCN2/CTGF, as well as in cardiac myocytes pretreated with recombinant human CCN2, causing reduced sensitivity of cardiac ß-adrenergic receptors to endogenous agonists. Furthermore, increased GRK5 in the heart initiates G protein-independent signaling by recruitment of ß-arrestin to the receptor allowing ß-arrestin to act as a scaffolding protein for signaling complexes at the plasma membrane such as the mitogen-activated protein kinase ERK1/2. These findings have been recapitulated in cardiac myocytes pretreated with recombinant human CCN2/CTGF. Yet, the signaling pathway(s) implicated in CTGF-induced induction of GRK5 expression in cardiac myocytes is yet to be characterized. Furthermore, the relative contribution of GRK5 to the cardioprotective actions afforded by CCN2/CTGF remains to be resolved.

Role of CCN proteins in regulation of tolerance towards ischemia-reperfusion injury and in the pathophysiology of heart failure.

Uncover the function of myocardial autocrine/paracrine factors or cytokines in the pathophysiology of heart failure. Current focus is on delineating the functions of secreted matricellular CCN proteins, in particular CCN1/Cyr61, CCN2/CTGF (connective tissue growth factor), and CCN5/WISP-2 (Wnt-inducible secreted protein-2), 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 non-structural proteins in the extracellular matrix considered to interact with structural extracellular matrix proteins, other growth factors, or cognate receptors on the cell surface. Yet, the mechanisms of CCN protein actions are poorly understood. We have established eukaryotic expression systems for production and purification of recombinant human CCN1, CCN2, and CCN5 in order to investigate the signaling mechanisms and biologic functions of these proteins in cardiac myocytes and cardiac fibroblasts. In addition, we are working with genetically-engineered mice in order to unravel the functions of CCN proteins in the cardiovascular system in vivo in health and in evolving heart failure


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