Leptin ameliorates ischemic- and LPS-induced damage in the heart of long-lived mice and in newborn rat cardiomyocytes - The 65th Annual Conference of the Israel Heart Society & The Israel Society of Cardiothoracic Surgery, 24-25 April 2018

heba abd alkhaleq The Cardiac Research Laboratory Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, center, Israel Ran Kornowski Cardiology, Rabin Medical Center, Petah Tikva, center, Israel Vadim Nudelman The Cardiac Research Laboratory Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, center, Israel Romy Zemel The Cardiac Research Laboratory Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, center, Israel Asher Shainberg The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, center, Israel Ruth Miskin Cardiology, Weizmann Institute of Science, Rehovot, center, Israel Edith Hochhauser The Cardiac Research Laboratory Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, center, Israel

Background: Leptin, spontaneously elevated in long-lived transgenic αMUPA mice, was previously shown to protect the heart against functional and inflammatory damage after myocardial infarction (MI).

Aims: 1. Investigate whether leptin could encounter also inflammatory damage in the heart after LPS injection, a model of general sepsis. 2. Test whether pretreatment with leptin could protect cardiomyocytes against hypoxia- and LPS-induced damage.

Methods: LPS was injected i.p. (20mg/Kg, 6h) to αMUPA and wild type (WT) control mice. Cardiomyocytes were treated with hypoxia (140 min) or LPS (40μg/ml, 24h). Expression of inflammatory-related genes or leptin was measured by RT-PCR. Cardiomyocyte toxicity was evaluated by staining for Reactive Oxygen Species (ROS) and measuring survival.

Results: LPS or MI considerably increased leptin expression in the αMUPA heart and liver, but not in the adipose tissue, where leptin expression was largely increased in WT mice. Expression of inflammatory cytokines TNFα and IL1-β was significantly lower in the αMUPA heart compared to the WT heart. In contrast, VEGF expression and angiogenesis significantly increased in the αMUPA heart. These changes were partly abrogated by leptin neutralizing antibodies, suggesting that the increased leptin expression in the αMUPA heart could lead to the aforementioned changes, possibly in an autocrine manner. In cardiomyocytes, both hypoxia and LPS elevated ROS levels, reduced survival staining, and increased the expression of gene encoding TNFα, IL-1β, Heme Oxygenase-1 (HO-1) and Hypoxia-Inducible Factor 1 (HIF-1α). Pretreatment with leptin (2μg/ml) for 5 h significantly reduced the levels of ROS and cytokine expression, however further elevated HO-1 and HIF-1α expression, and increased survival staining.

Conclusions: Leptin pretreatment can exert in cardiomyocytes a preconditioning state, possibly involving HO-1 and HIF-1α, which attenuates ROS-induced toxicity, thus increasing cell survival. Similarly, increased leptin expression in the αMUPA heart after LPS administration could generate a pro-survival state, as previously shown after MI.