Journal of cardiovascular medicine (Hagerstown, Md.) · 2021
Paradoxical effect of fat diet in matrix metalloproteinases induced mitochondrial dysfunction in diabetic cardiomyopathy.
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Gliozzi Micaela, Scarano Federica, Musolino Vincenzo, Carresi Cristina, Scarcella Antonino, Nucera Saverio, Scicchitano Miriam, Ruga Stefano, Bosco Francesca, Maiuolo Jessica, Macrì Roberta, Zito Maria Caterina, Oppedisano Francesca, Guarnieri Lorenza, Mollace Rocco, Palma Ernesto, Muscoli Carolina, Mollace Vincenzo
Аннотация
AIMS: Diabetic cardiomyopathy represents the main cause of death among diabetic people. Despite this evidence, the molecular mechanisms triggered by impaired glucose and lipid metabolism inducing heart damage remain unclear. The aim of our study was to investigate the effect of altered metabolism on the early stages of cardiac injury in experimental diabetes.
METHODS: For this purpose, rats were fed a normocaloric diet (NPD) or a high fat diet (HFD) for up to 12 weeks. After the fourth week, streptozocin (35 mg/kg) was administered in a subgroup of both NPD and HFD rats to induce diabetes. Cardiac function was analysed by echocardiography. Matrix metalloproteinases (MMPs) activity and intracellular localization were assessed through zymography and immunofluorescence, whereas apoptotic and oxidative markers by immunohistochemistry and western blot.
RESULTS: Hyperglycaemia or hyperlipidaemia reduced ejection fraction and fractional shortening as compared with control. Unexpectedly, cardiac dysfunction was less marked in diabetic rats fed a hyperlipidaemic diet, suggesting an adaptive response of the myocardium to hyperglycaemia-induced injury. This response was characterized by the inhibition of N-terminal truncated-MMP-2 translocation from endoplasmic reticulum into mitochondria and by superoxide anion overproduction observed in cardiomyocytes under hyperglycaemia.
CONCLUSION: Overall, these findings suggest novel therapeutic targets aimed to counteract mitochondrial dysfunction in the onset of diabetic cardiomyopathy.
METHODS: For this purpose, rats were fed a normocaloric diet (NPD) or a high fat diet (HFD) for up to 12 weeks. After the fourth week, streptozocin (35 mg/kg) was administered in a subgroup of both NPD and HFD rats to induce diabetes. Cardiac function was analysed by echocardiography. Matrix metalloproteinases (MMPs) activity and intracellular localization were assessed through zymography and immunofluorescence, whereas apoptotic and oxidative markers by immunohistochemistry and western blot.
RESULTS: Hyperglycaemia or hyperlipidaemia reduced ejection fraction and fractional shortening as compared with control. Unexpectedly, cardiac dysfunction was less marked in diabetic rats fed a hyperlipidaemic diet, suggesting an adaptive response of the myocardium to hyperglycaemia-induced injury. This response was characterized by the inhibition of N-terminal truncated-MMP-2 translocation from endoplasmic reticulum into mitochondria and by superoxide anion overproduction observed in cardiomyocytes under hyperglycaemia.
CONCLUSION: Overall, these findings suggest novel therapeutic targets aimed to counteract mitochondrial dysfunction in the onset of diabetic cardiomyopathy.