Application of a Novel Curcumin Analog in the Management of Diabetic Cardiomyopathy

Diabetes mellitus is becoming an epidemic health threat and represents one of the most prevalent chronic noncommunicable disorders. Cardiovascular complications are considered the leading cause of death for diabetic patients. Diabetes leads to undesired changes in cardiac structure and function, a condition commonly known as diabetic cardiomyopathy, which occurs independent of macroand microvascular comorbidities in diabetes (1,2). Both systolic and diastolic dysfunctions have been demonstrated in diabetic hearts including prolonged duration of contraction and relaxation, reduced velocity of contraction and relaxation, and depressed myocardial contractility (1,3). In particular, clinical evaluation using electrocardiogram and echocardiography has revealed substantial functional changes in diabetic hearts, including shorter left ventricular ejection time, prolonged preejection duration, increased wall stiffness, decreased fractional shortening, decreased rate of left ventricular filling, and increased action potential duration (4,5). To date, a plethora of cellular and molecular mechanisms have been postulated for the onset and development of diabetic cardiomyopathy, including reduced energy production due to decreases in mitochondrial respiration and pyruvate dehydrogenase activity, accumulation of reactive oxygen species, oxidative stress, apoptosis, impaired autophagy, and malfunction of cardiac contractile and intracellular Ca regulatory proteins such as myosin, sarco/ endoplasmic reticulum Ca-ATPase (SERCA), and Na-Ca exchanger (1–3,5,6). The high morbidity and mortality for diabetic cardiomyopathy warrant aggressive clinical management involving lifestyle modification, control of glucose and lipid abnormalities, and treatment of hypertension and coronary artery diseases, if present. The commonly used therapeutic regimes in diabetic patients with heart anomalies encompass ACE inhibitors, digoxin, diuretics, b-blockers, Ca antagonists, and spironolactone (7). Nonetheless, the mortality rate for diabetic cardiomyopathy still remains high, warranting novel and effective therapeutic strategies. In this issue, Pan et al. (8) extended their earlier work revealing that C66 [(2E,6E)-2,6-bis(2-(trifluoromethyl) benzylidene) cyclohexanone], a curcumin analog, reduces streptozotocin-induced hypertriglyceridemia in both serum and hearts, in addition to the significantly reduced plasma and cardiac triglyceride levels. The authors further reported that reduction in hyperlipidemia in response to C66 therapy is accompanied by improved cardiac function, inhibition of Jun NH2-terminal kinase (JNK) signaling and cardiac inflammation in the type 1 experimental diabetic model. Pretreatment with C66 inhibited a high glucose2induced rise in proinflammatory cytokines via inactivation of nuclear factor kB (NF-kB). Furthermore, they showed that inhibition of JNK phosphorylation may be responsible for the beneficial effect of C66 against inflammation and apoptosis. In diabetic mice, administration of C66 or another JNK inhibitor SP600125 effectively lowered plasma and cardiac levels of tumor necrosis factor (TNF)-a, accompanied by lessened apoptosis and improved histology, including interstitial fibrosis and functional anomalies in the heart. These findings support the notion that the curcumin analog protects against diabetes and hyperglycemia-induced cardiac damage via inhibition of inflammation. More important, these findings depict a critical role for JNK activation in diabetic cardiac injury and suggest that JNK may be considered as a therapeutic target for diabetic cardiomyopathy. A recent report from the same group indicated that C66 is capable of preventing JNK activation in diabetes, leading to protection against diabetes-induced cardiac fibrosis, oxidative stress, endoplasmic reticulum (ER)