1610-P: Cardiomyocyte N-acetyltransferase 10 Overexpression Protects against Diabetic Cardiomyopathy

Introduction & Objective: Diabetic cardiomyopathy is a major complication and a leading cause of death in patients with diabetes. Treatment specific to improve outcomes of diabetic cardiomyopathy is lacking. Iron overload-induced cell death, known as ferroptosis, contributes to the development of diabetic cardiomyopathy. N-acetyltransferase (NAT10), the only known writer of N4-acetylcytidine, has been implicated in myocardial ischemia reperfusion and heart failure. However, the role of NAT10 in diabetic cardiomyopathy and its regulatory effect on ferroptosis in diabetic cardiomyopathy, are unclear.

Methods: Six-week-old wild-type mice were subjected to either chow diet or high-fat (HFD) diet feeding and injection of streptozotocin (STZ) to induce diabetic cardiomyopathy. Some of the mice were injected with AAV9 encoding cardiac troponin-T (cTnT)-driven NAT10 to overexpress NAT10 in cardiomyocytes (CMs).

Results: Mice treated with HFD+STZ exhibited decreased E/A (Chow: 1.547±0.17 vs HFD+STZ: 1.166±0.07, p<0.05, n=8) and reduced global longitudinal strain as well as decreased fractional shortening (FS, Chow: 45.72%±3.18 vs HFD+STZ: 38.32%±2.04, p=0.04, n=8) and a ~50% downregulation of cardiac NAT10 protein expression (p<0.05). These changes were associated with a 3-fold increase in iron accumulation in the heart (p<0.01). In HFD+STZ mice, CM-specific NAT10 overexpression increased E/A (Control: 1.11±0.13 vs Overexpression: 1.47±0.11, p<0.01, n=8) and FS (Control: 37.06 %±4.22: vs Overexpression: 43.58%±4.57) as well as reduced iron accumulation in the heart. In CMs exposed to high glucose and palmitate, lentiviral overexpression of NAT10 reduced while its gene knockdown increased cell death and markers of ferroptosis as well as oxidative stress (all p<0.05).

Conclusion: NAT10 protects the heart against diabetic cardiomyopathy through reducing ferroptosis. NAT10 is a promising therapeutic target in preventing diabetic cardiomyopathy.