Organ Targeted Copper Delivery Reverses Fibrosis in Rhesus Monkey Model of Myocardial Ischemic Infarction

Abstract

Excessive collagen deposition post myocardial ischemic injury hastens heart failure. Copper supplementation significantly improved cardiac function and reduced fibrosis in myocardial ischemic infarction. The present study was undertaken to understand the link between the reduced fibrosis and the recovery of cardiac function. Male Rhesus monkeys of 4–5 years old were subjected to coronary artery ligation to induce myocardial infarction. At the end of fourth weeks after the surgery, ultrasound contrast microbubble composed of Cu‐albumin coating for cardiac organ‐specific Cu delivery through ultrasound manipulation was used to treat the monkeys twice a week for other four weeks. Collagen deposition in the infarct hearts was observed 4 weeks and further enhanced 8 weeks after ischemia. The collagen content in the infarct myocardium was not changed significantly after Cu treatment. However, type I and III collagen mRNA levels were decreased, and collagen network became loosened, along with an increase in the capillary density. Lysyl oxidase (LOX), an enzyme related to collagen deposition, was increased, and metalloproteinase‐1 (MMP‐1), an enzyme involved in collagen degradation, was decreased in the infarct area relative to sham operated control and remote area. After Cu treatment, MMP‐1 was significantly increased, and the ratio between MMP‐1/LOX was dramatically elevated. These results thus suggest Cu‐induced MMP‐1 elevation in the infarct area is mostly likely responsible for the breakage of collagen cross‐linking leading to diminished collagen deposition and improved angiogenesis and recovery of cardiac function.Support or Funding InformationThis study is supported by National Science Foundation of China (81230004 and 81300109).