Mechanisms of glucotoxicity in the heart

Hyperglycemia is a powerful indicator of mortality in patients with acute myocardial infarction. Hyperglycemia might also result in toxic effects in cardiomyocytes. Indeed, it modifies myofribrillar structure and intercellular connections and induces cell death by an oxidative stress-dependent mechanism. Exposure to high glucose (HG) stimulates reactive oxygen species (ROS) production through NOX2 activation, the major isoform of NADPH oxidase in cardiomyocytes. This activation depends on Rac1 activation, a subunit of NOX2. The underlying mechanism responsible for NOX2 activation remains elusive. In this study, we have dissected the link between glucose transport, its metabolism, and NOX2 activation under hyperglycemic conditions in primary cultured rat cardiomyocytes. HG exposure activated Rac1GTP and induced p47phox translocation to the plasma membrane resulting in NADPH oxidase (NOX2) activation, increased ROS production, insulin resistance and eventually cell death. NADPH produced by the pentose phosphate pathway (PPP) is required for NADPH oxidase-dependent ROS generation; however NADPH is not sufficient to explain NOX2 activation in terms of Rac-1 activation and p47phox translocation. NOX2 activation depends on a sodium/glucose cotransporter (SGLT) type of transport which is located in the caveolae. Glucotoxicity is a rapid phenomenon that is compartmentalized since several proteins of interest including SGLT, phospho-ERM and p47phox are found close to caveolin 3. Our mechanism of glucotoxicity is counteracted by A-769662 or activated protein C which activates AMPK, kinase involved in many cellular processes including glucose metabolism. The major finding of this work is that increased glucose metabolism by itself does not trigger NADPH oxidase activation, although PPP is necessary to provide NOX2 with NADPH and to produce ROS. Moreover, glucose transport through the classical facilitated glucose transporters (GLUTs) is not required to induce glucotoxicity. NOX2 activation results from glucose transport through SGLT thus transducing a metabolic signal into an intracellular ionic signal. SGLT acts as a glucose sensor in the heart and could be therefore considered as a potential therapeutic target. SGLT1 activates an ERM-dependent signaling cascade located in the caveolar structure leading to NOX2 activation. Sub-cellular compartmentalization into caveolae is critical for cardiac glucotoxicity. AMPK stimulation protects cardiomyocytes against glucotoxicity and seems therefore a good therapeutic candidate.(SBIM 3) -- UCL, 201