TY - JOUR
T1 - Cardioprotective Effects of 1-(3,6-Dibromo-carbazol-9-yl)-3-Phenylamino-Propan-2-Ol in Diabetic Hearts via Nicotinamide Phosphoribosyltransferase Activation
AU - Tur, Jared
AU - Badole, Sachin L.
AU - Manickam, Ravikumar
AU - Chapalamadugu, Kalyan C.
AU - Xuan, Wanling
AU - Guida, Wayne
AU - Crews, Jaret J.
AU - Bisht, Kirpal S.
AU - Tipparaju, Srinivas M.
N1 - Funding Information:
The study is supported in part by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK119066] (to S.M.T.) and Saunders Endowment (to S.M.T.). No author has an actual or perceived conflict of interest with the contents of this article. S.M.T. is coholder of U.S. patent WO/2017/161261 AI.
Publisher Copyright:
© 2022 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Diabetes is associated with increased cardiac injury and sudden death. Nicotinamide phosphoribosyltransferase (Nampt) is an essential enzyme for the NAD1 salvage pathway and is dysregulated in diabetes. Nampt activation results in rescued NADH/NAD1 ratios and provides pharmacological changes necessary for diabetic cardioprotection. Computer docking shows that 1-(3,6-Dibromo-carbazol-9-yl)-3-phenylamino-propan-2-ol (P7C3) allows for enhanced Nampt dimerization and association. To test the pharmacological application, we used male leptin receptor–deficient (db/db) mice and treated them with Nampt activator P7C3. The effects of 4-week P7C3 treatment on cardiac function were evaluated along with molecular signaling changes for phosphorylated protein kinase B (p-AKT), phosphorylated endothelial nitric oxide synthase (p-eNOS), and sirtuin 1 (SIRT1). The cardiac function evaluated by ECG and echocardiography were significantly improved after 4 weeks of P7C3 treatment. Biochemically, higher NADH/NAD1 ratios in diabetic hearts were rescued by P7C3 treatment. Moreover, activities of Nampt and SIRT1 were significantly increased in P7C3-treated diabetic hearts. P7C3 treatment significantly decreased the blood glucose in diabetic mice with 4-week treatment as noted by glucose tolerance test and fasting blood glucose measurements compared with vehicle-treated mice. P7C3 activated Nampt enzymatic activity both in vitro and in the 4-week diabetic mouse hearts, demonstrating the specificity of the small molecule. P7C3 treatment significantly enhanced the expression of cardioprotective signaling of p-AKT, p-eNOS, and Beclin 1 in diabetic hearts. Nampt activator P7C3 allows for decreased infarct size with decreased Troponin I and lactose dehydrogenase (LDH) release, which is beneficial to the heart. Overall, the present study shows that P7C3 activates Nampt and SIRT1 activity and decreases NADH/ NAD1 ratio, resulting in improved biochemical signaling providing cardioprotection.
AB - Diabetes is associated with increased cardiac injury and sudden death. Nicotinamide phosphoribosyltransferase (Nampt) is an essential enzyme for the NAD1 salvage pathway and is dysregulated in diabetes. Nampt activation results in rescued NADH/NAD1 ratios and provides pharmacological changes necessary for diabetic cardioprotection. Computer docking shows that 1-(3,6-Dibromo-carbazol-9-yl)-3-phenylamino-propan-2-ol (P7C3) allows for enhanced Nampt dimerization and association. To test the pharmacological application, we used male leptin receptor–deficient (db/db) mice and treated them with Nampt activator P7C3. The effects of 4-week P7C3 treatment on cardiac function were evaluated along with molecular signaling changes for phosphorylated protein kinase B (p-AKT), phosphorylated endothelial nitric oxide synthase (p-eNOS), and sirtuin 1 (SIRT1). The cardiac function evaluated by ECG and echocardiography were significantly improved after 4 weeks of P7C3 treatment. Biochemically, higher NADH/NAD1 ratios in diabetic hearts were rescued by P7C3 treatment. Moreover, activities of Nampt and SIRT1 were significantly increased in P7C3-treated diabetic hearts. P7C3 treatment significantly decreased the blood glucose in diabetic mice with 4-week treatment as noted by glucose tolerance test and fasting blood glucose measurements compared with vehicle-treated mice. P7C3 activated Nampt enzymatic activity both in vitro and in the 4-week diabetic mouse hearts, demonstrating the specificity of the small molecule. P7C3 treatment significantly enhanced the expression of cardioprotective signaling of p-AKT, p-eNOS, and Beclin 1 in diabetic hearts. Nampt activator P7C3 allows for decreased infarct size with decreased Troponin I and lactose dehydrogenase (LDH) release, which is beneficial to the heart. Overall, the present study shows that P7C3 activates Nampt and SIRT1 activity and decreases NADH/ NAD1 ratio, resulting in improved biochemical signaling providing cardioprotection.
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U2 - 10.1124/jpet.122.001122
DO - 10.1124/jpet.122.001122
M3 - Article
C2 - 35680376
AN - SCOPUS:85135598368
VL - 382
SP - 233
EP - 245
JO - The Journal of pharmacology and experimental therapeutics
JF - The Journal of pharmacology and experimental therapeutics
SN - 0022-3565
IS - 2
ER -