Roles of PICOT and CCN5 in cardiac remodeling

Abstract

Part I. PICOT alleviates myocardial ischemia-reperfusion injury by reducing intracellular levels of reactive oxygen species Excessive generation of reactive oxygen species (ROS) is one of the main causes of myocardial ischemia reperfusion (I/R) injury. In this study, I investigated the role of protein kinase C-interacting cousin of thioredoxin (PICOT; Grx3) during myocardial I/R using PICOT transgenic (TG) and knockdown (KD) mice. Infarction and apoptosis were attenuated in PICOT TG mice but exacerbated in PICOT KD mice upon I/R. In parallel, I/R-induced generation of ROS was attenuated in PICOT TG mice but exacerbated in PICOT KD mice. Angiotensin II (AngII)-mediated increases in ROS and free iron levels were also attenuated in cardiomyocytes isolated from PICOT TG mice but exacerbated in cardiomyocytes from PICOT KD mice. Accordingly, H2O2-mediated cell death was attenuated in cardiomyocytes isolated from PICOT TG mice but exacerbated in cardiomyocytes from PICOT KD mice. Taken together, these data show that PICOT alleviates myocardial I/R injury by regulating intracellular ROS and free iron levels. I suggest that PICOT presents a novel therapeutic strategy for myocardial I/R injury.

Part II. CCN5 knockout mice exhibit lipotoxic cardiomyopathy with mild obesity and diabetes Obesity is associated with various human disorders, such as type 2 diabetes, cardiovascular diseases, hypertension, and cancers. In this study, I observed that knockout (KO) of CCN5, which encodes a matricellular protein, caused mild obesity in mice. The CCN5 KO mice also exhibited mild diabetes characterized by high fasting glucose levels and impaired insulin and glucose tolerances. Cardiac hypertrophy, ectopic lipid accumulation, and impaired lipid metabolism in hearts were observed in the CCN5 KO mice, as determined using histology, quantitative real time RT-PCR, and western blotting. Fibrosis was significantly greater in hearts from the CCN5 KO mice both in interstitial and perivascular regions, which was accompanied by higher expression of pro-fibrotic and pro-inflammatory genes. Both systolic and diastolic functions were significantly impaired in hearts from the CCN5 KO mice, as assessed using echocardiography. Taken together, these results indicate that CCN5 KO leads to lipotoxic cardiomyopathy with mild obesity and diabetes in mice.