Role of Gremlins in the Aortic Arch of Spontaneously Hypertensive and Hyperlipidemic Rats

Abstract

: Atherosclerosis is a lifestyle-related disease that plays a major role in cardiovascular disease. Recently, we found that gene expression of Gremlin 2, an antagonist of bone morphogenetic protein BMP , was signi cantly increased in the aorta of spontaneously hypertensive and hyperlipidemic rats SHHRs fed a highfat, 30 sucrose solution diet HFDS . However, the role of Gremlin 1 Grem1 and Gremlin 2 Grem2 in the aortic arch of rats under hypertensive, hyperlipidemic, and hyperglycemic conditions remains unclear. Therefore, in the present study we investigated the molecular role of Gremlins in the aorta of SHHRs. Four-month-old male Sprague-Dawley rats and SHHRs were fed a normal diet or the HFDS ad libitum for 4 months. Then, gene and protein expression was analyzed using quantitative polymerase chain reaction and western blotting, respectively. Grem1 and Grem2 protein expression was increased, whereas phosphorylated Smad1/5 protein expression was low, in the aorta of SHHRs fed the HFDS. In addition, the expression of the downstream gene targets of BMP, namely inhibitor of DNA binding 1 Id1 and atonal homolog 8 Atoh8 , was decreased in aortas of SHHRs fed the HFDS. Furthermore, mRNA expression of Snail, -smooth muscle actin SMA , and Fibronectin was increased in SHHRs fed the HFDS. These ndings suggest that upregulation of Gremlins attenuates the activation of BMP signaling, which contributes to brogenesis of the aorta.