The Role of Leptin in Coronary Collateral Growth

Abstract

Leptin is an adipokine that is conventionally thought to have its major effects on appetite suppression, but more recently it is suggested to have a variety cardiovascular effects including on vascular growth. The Zucker obese fatty (ZOF) rat is a model of dysfunctional leptin signaling due to a mis‐sense mutation of the leptin receptor. This mutation leads to hyperphagia inducing dietary‐induced obesity and phenotypes consistent with the metabolic syndrome, e.g., obesity, hypercholesterolemia, hyperglycemia, and hyperlipidemia. Previously we observed abrogated coronary collateral growth (CCG) in ZOF rats, but we did not determine if this deficiency is directly due to the mis‐sense mutation in leptin, which could negatively impact the vasculature, or indirectly related to the hyperphagia‐induced metabolic syndrome. To resolve between these two possibilities, we studied CCG in young ZOF rats prior to the development of obesity and the alterations in blood chemistries. CCG was stimulated by repetitive episodes of myocardial ischemia (RI) induced by chronic implantation of a pneumatic snare around the left anterior descending artery (LAD), which was performed during a left thoracotomy. Pressurization of the snare induced occlusion of the LAD and a total of 24 occlusions were performed throughout the day. CCG in rats was assessed by the measurement of myocardial blood flow (MBF) using contrast echocardiography at Day 0 (prior to the initiation of RI) and after 10 days of RI in the normal and collateral‐dependent regions; and is presented as a ratio of collateral zone/normal zone flow (CZ/NZ). In old (6–9 months, n=8) and young (3–4 months, n=4) ZOF rats, the CZ/NZ ratios at Day 0 were 0.15±.03, and 0.22±0.04, respectively (P=NS). This indicates that the native collateral circulation was comparable in the two groups. In contrast, following 10 days of RI, the CZ/NZ flow ratio was unchanged (from Day 0) in the old ZOF rats (0.17±0.05), but significantly increased in the young ZOF rats (0.78±0.07; P<0.05 vs Day 0 and old ZOF). To eliminate the possibility that the differences are related to the ages of the ZOF rats, age‐matched Lean controls were studied. The CZ/NZ ratios were equal in the young and old lean rats suggesting that the difference in the ZOF rats is not related to age. Based on these results we conclude that the reason why CCG is impaired in ZOF rats is not due to an absence of leptin signaling; rather the impaired coronary collateral growth in ZOF rats is likely related to the myriad cardiovascular risk factors associated with the metabolic syndrome.Support or Funding InformationThis work was supported by NIH/NHLBI (HL100828Z and HL83366), Fibus Family Foundation, Frances Schermer Charitable Trust & The Lillian Schermer Charitable Trust, and the Joy Cone Company to W.M.C.; NIH/NHLBI (HL115114) to LY.