Abstract
BackgroundDiabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin—SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2.MethodsCardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12–14 weeks old WT or db/db mice (n = 4–8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5–33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1.ResultsAngiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium–calcium exchanger (NCX) and the sodium–hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment.ConclusionDapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.
Highlights
Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease
Obesity, insulin resistance and impaired glucose tolerance are associated with increased intramyocardial levels of lipid which results in lipotoxicity, diastolic dysfunction, cardiac electrical disturbances and Ca2+ dysregulation [3, 4]
Animal model DAPA attenuates metabolic dysfunction and diabetic cardiomyopathy Diabetic mice had elevated body weight, increased glucose level but normal heart weight, glucose and cholesterol blood levels when compared to wild type (WT) animals (Table 1)
Summary
Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Patients with diabetes are two to three times more likely to develop cardiovascular disease and are at an increased risk of having a myocardial infarction, stroke or develop heart failure [1, 2]. Once cardiovascular disease has developed, diabetic patients have a significantly worse prognosis compared to non-diabetic ones. Long-term exposure to oxidative stress in diabetes mellitus induces chronic inflammation and fibrosis [5]. The expression of TNF-α and NF-κB along with collagen were elevated and accompanied by an increase in oxidative stress in the diabetic heart [6]. ATII promotes cardiac hypertrophy, inflammation, and fibrosis [7]
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