While the thermogenic properties of brown adipose tissue (BAT) are well known, we recently reported previously unknown cardioprotective properties of BAT against catecholamine-induced myocardial injury. In preliminary studies that support the present proposal, we identified bone morphogenetic protein 3b (BMP- 3b) as a cardioprotective adipokine that may mediate BAT-related cardioprotection. The objective of this proposal is to further investigate the cardioprotective effects of BAT and BMP-3b in a murine model of myocardial ischemia-reperfusion (I/R) injury. In preliminary studies, we demonstrated that mice that are deficient in the uncoupling protein 1 (UCP1), a protein synthetized by BAT and required for BAT thermogenic function, develop greater myocardial infarction (MI) size than WT mice after I/R injury. We identified BMP-3b, a protein of previously unknown cardiovascular properties, as an adipokine synthesized and secreted by the activated BAT of WT but not of UCP1-deficient mice. We demonstrated that BMP-3b treatment decreased MI size after I/R injury in WT mice. In preliminary studies, BMP-3b increased the levels of P-Smad1/5/8 and S1177P-NOS3, and decreased apoptosis in serum-deprived cardiomyocytes (CMs). Furthermore, BMP-3b increased left ventricular (LV) P-Smad1/5/8 and STAT3 levels after I/R. To further investigate the cardioprotective role of BAT in I/R injury, 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. By studying BMP-3b-/- and BAT-specific BMP-3b-/- mice, we will elucidate whether BMP-3b is the adipokine in BAT, and BAT the BMP-3b producing tissue that is required to limit I/R injury. To investigate the mechanisms underlying the cardioprotective effects of BMP-3b, the role of the BMP, NOS3 and STAT3 pathways in the cardioprotective effect of BMP-3b will be assessed using both isolated mouse adult CMs and the in vivo I/R murine model. The CM receptors engaged by BMP-3b will be identified. As a first step toward applying the results to humans, we will investigate whether BMP-3b is secreted by human brown adipocytes, and whether myocardial infarction increases BMP-3b in the plasma of human patients. To further investigate the potential clinical applicability of BMP-3b treatment in I/R injury, we will test the effect 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 injury.
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, will test whether human brown fat cells also make BMP-3b, and whether BMP-3b increases in the blood after a heart attack.
|Lindsey, Merry L; Kassiri, Zamaneh; Virag, Jitka A I et al. (2018) Guidelines for measuring cardiac physiology in mice. Am J Physiol Heart Circ Physiol 314:H733-H752|