Alterations in Glucose Metabolism During the Transition to Heart Failure: The Contribution of UCP-2

Abstract

The cardiac expression of the mitochondrial uncoupling protein (UCP)-2 is increased in patients with heart failure. However, the underlying causes as well as the possible consequences of these alterations during the transition from hypertrophy to heart failure are still unclear. To investigate the role of UCP-2 mechanistically, expression of UCP-2 was silenced by small interfering RNA in adult rat ventricular cardiomyocytes. We demonstrate that a downregulation of UCP-2 by siRNA in cardiomyocytes preserves contractile function in the presence of angiotensin II. Furthermore, silencing of UCP-2 was associated with an upregulation of glucose transporter type (Glut)-4, increased glucose uptake, and reduced intracellular lactate levels, indicating improvement of the oxidative glucose metabolism. To study this adaptation in vivo, spontaneously hypertensive rats served as a model for cardiac hypertrophy due to pressure overload. During compensatory hypertrophy, we found low UCP-2 levels with an upregulation of Glut-4, while the decompensatory state with impaired function was associated with an increase of UCP-2 and reduced Glut-4 expression. By blocking the aldosterone receptor with spironolactone, both cardiac function as well as UCP-2 and Glut-4 expression levels of the compensated phase could be preserved. Furthermore, we were able to confirm this by left ventricular (LV) biopsies of patients with end-stage heart failure. The results of this study show that UCP-2 seems to impact the cardiac glucose metabolism during the transition from hypertrophy to failure by affecting glucose uptake through Glut-4. We suggest that the failing heart could benefit from low UCP-2 levels by improving the efficiency of glucose oxidation. For this reason, UCP-2 inhibition might be a promising therapeutic strategy to prevent the development of heart failure.

Swiprosin-1/EFhD-2 Expression in Cardiac Remodeling and Post-Infarct Repair: Effect of Ischemic Conditioning

“…On the other hand, increased expression of rno-miR-32-3p was inversely correlated with the expression of sarcomeric proteins (MHC-α, troponin T), transporters of sodium (NCX, Scl5a3), and that of fatty acid metabolism (HADHA, UCP-2). While HADHA is required for fatty acid metabolism, down-regulation of UCP-2 will favor glucose utilization [23]. Therefore, the down-regulation of HADHA and UCP-2 both initiate a metabolic switch into the direction of glucose metabolism.…”

MicroRNA‑138‑5p drives the progression of heart failure via inhibiting sirtuin 1 signaling

“…The biological functions of SIRT1 in the process of HF have been previously identified ( 33 ). For instance, SIRT1 can modify mitochondrial function and increase ATP production by deacetylating histone and mitochondrial proteins (i.e., UCP-2 and PGC-1α), thereby improving cardiomyocyte metabolism and alleviating the process of HF ( 7 , 34 ). Through deacetylating FOXO1, SIRT1 is responsible for activating Rab7, and thus, it exerts its protective effect on starvation-induced moribund myocardium via blocking apoptosis and clearing damaged mitochondria ( 35 , 36 ).…”

Mitochondrial ion channels in cardiac function

“…UCP1 is chiefly localized to the brown adipose tissue, UCP2 is present in the heart and UCP-3 is present in skeletal muscles. In the heart, loss of UCP2 from fibroblasts results in loss of right ventricular function upon pressure overload (213), however, in heart failure, UCP-2 inhibition in cardiomyocytes is beneficial as it improves the efficiency of glucose oxidation (214). In failing rat hearts, levels of UCP2 increase in pressure overload (215) and after myocardial infarction (216).…”