CPUY11018, an azimilide derivative, ameliorates isoproterenol-induced cardiac insufficiency through relieving dysfunctional mitochondria and endoplasmic reticulum.

Li, Meng; Tang, Yi‐Qun; Du, Rong‐Hui; Shi, Fang‐Hong; Hussein, Humed Khan; Dai, De‐Zai; Dai, Yin

Objectives Deterioration of cardiac performance under stress may be partly mediated by dysfunctional mitochondria and endoplasmic reticulum ( ER) that is likely related to an activation of NADPH oxidase ( NOX) and an increase in pro-inflammatory factors. We investigated if a new compound CPUY11018 ( CPUY) derived from Azimilide could ameliorate the stress impaired cardiac performance. Methods Forty-eight male Sprague Dawley rats were randomly divided into six groups and were injected with isoproterenol ( ISO, 1 ml/kg, s.c.) for 10 days. Cardiac myocytes and fibroblasts from neonate rats were incubated with ISO. CPUY was employed and compared with apocynin ( APO) - an inhibitor of NOX. Key findings In ISO-treated group, the compromised haemodynamics and cardiac remodelling were significant with dysfunctional mitochondria indicated by decreased MnSOD and mitochondrial membrane potential, and an enhanced reactive oxygen species genesis. Downregulation of FKBP12.6, CASQ2 and SERCA2a was also remarkable in vivo and in vitro implying an abnormal ER. Upregulated Nox4, p22phox and p47phox were significant, associated with upregulation of Src, Iκ Bβ and NFκ B, and downregulation of pAMPK/ AMPK and Cx40 in vivo and in vitro. These abnormalities were relieved by CPUY and APO. Conclusions CPUY is potential in managing cardiac insufficiency through normalizing mitochondria and ER in the affected heart.

HEART failure treatment; ISOPROTERENOL; MITOCHONDRIAL physiology; ENDOPLASMIC reticulum; NADPH oxidase; PIPERAZINE

Journal of Pharmacy & Pharmacology, 2015, Vol 67, Issue 8, p1029

0022-3573

Academic Journal

10.1111/jphp.12401