While the thermogenic properties of brown adipose tissue (BAT) are well known, we recently discovered previously unknown cardioprotective properties of BAT. Mice deficient in the uncoupling protein 1 (UCP1), a protein synthetized by BAT and required for BAT thermogenic function, developed increased cardiomyocyte (CM) injury in a model of catecholamine-induced cardiomyopathy. Cardiomyocyte injury was decreased by transplantation of BAT from WT mice into UCP1-deficient (UCP1-/-) mice, suggesting that functional BAT protects against catecholamine-induced cardiac injury. In Preliminary Studies, we demonstrated that UCP1-/- mice (with dysfunctional BAT) developed greater myocardial infarction (MI) size than WT mice and had a lower level of left ventricular (LV) phosphorylated endothelial nitric oxide synthase (S1177P-NOS3) after ischemia- reperfusion (I/R) injury. We identified bone morphogenetic protein 3b (BMP-3b) as an adipokine secreted by BAT that may mediate BAT-related cardioprotection. BMP-3b increased S1177P-NOS3, decreased apoptosis in serum-deprived rat neonatal CMs and decreased MI size after I/R in WT mice in vivo. The objective of the proposed research is to investigate the cardioprotective effects of BAT and BMP-3b in cardiac I/R injury. To further investigate the cardioprotective role of BAT in I/R injury, we will determine whether UCP1- deficiency induces greater adverse LV remodeling after I/R injury, independent of MI size. We will determine whether restoring functional BAT in UCP1-/- mice and increasing functional BAT in WT mice limit MI size. In these studies, we will transplant BAT from WT mice into UCP1-/- and WT mice prior to myocardial injury. Using CM- specific NOS3-/- mice, we will explore the role of the NOS3 pathway in the cardioprotective effect of BAT. By studying BMP-3b-/- mice, we will elucidate the role of BMP-3b in I/R injury and whether BMP-3b is the adipokine in BAT that is required to limit I/R injury by studying BMP-3b-/- mice. Finally, we will investigate the mechanisms underlying the cardioprotective effects of BMP-3b and explore the potential role of BMP-3b as a treatment for I/R induced CM injury. We will assess the role of the NOS3 pathway in the cardioprotective effect of BMP-3B using both isolated mouse adult CMs and the in vivo I/R model in WT, BMP-3b-/- and CM-specific NOS3-/- mice. As a first step toward applying the results to humans, we will investigate whether BMP-3b is secreted by human brown adipocytes. We will test the effects of varying BMP-3b dose, and time of delivery relative to onset of injury, on the extent of myocardial damage in the in vivo murine I/R model. Successful completion of these aims will define and elucidate a novel cardioprotective effect of BAT in myocardial I/R injury and will characterize a previously unknown cardioprotective adipokine secreted by BAT, BMP-3b. The proposal is a first step toward identifying new cardioprotective therapies that may decrease myocardial I/R.
The experiments proposed in this application study the previously unknown beneficial effect of a tissue, brown fat, and of one protein made by this tissue and released in the blood, BMP-3b, in protecting the heart against the heart damage created by heart attacks. We will understand by which mechanisms the tissue and the protein are protective in mice. In first steps towards application in humans, we will optimize BMP-3b treatment to protect the heart, and will test whether human brown fat cells also make BMP-3b.
