α-Melanocyte-stimulating hormone alleviates pathological cardiac remodeling via melanocortin 5 receptor.

α-Melanocyte-stimulating hormone (α-MSH) regulates diverse physiological functions by activating melanocortin receptors (MC-R). However, the role of α-MSH and its possible target receptors in the heart remain completely unknown. Here we investigate whether α-MSH could be involved in pathological cardiac remodeling. We found that α-MSH was highly expressed in the mouse heart with reduced ventricular levels after transverse aortic constriction (TAC). Administration of a stable α-MSH analog protected mice against TAC-induced cardiac hypertrophy and systolic dysfunction. In vitro experiments revealed that MC5-R in cardiomyocytes mediates the anti-hypertrophic signaling of α-MSH. Silencing of MC5-R in cardiomyocytes induced hypertrophy and fibrosis markers in vitro and aggravated TAC-induced cardiac hypertrophy and fibrosis in vivo. Conversely, pharmacological activation of MC5-R improved systolic function and reduced cardiac fibrosis in TAC-operated mice. In conclusion, α-MSH is expressed in the heart and protects against pathological cardiac remodeling by activating MC5-R in cardiomyocytes. These results suggest that analogs of naturally occurring α-MSH, that have been recently approved for clinical use and have agonistic activity at MC5-R, may be of benefit in treating heart failure.

Dynamic Micropatterning Reveals Substrate-Dependent Differences in the Geometric Control of Cell Polarization and Migration.

Cells are highly dynamic and adopt variable shapes and sizes. These variations are biologically important but challenging to investigate in a spatiotemporally controlled manner. Micropatterning, confining cells on microfabricated substrates with defined geometries and molecular compositions, is a powerful tool for controlling cell shape and interactions. However, conventional binary micropatterns are static and fail to address dynamic changes in cell polarity, spreading, and migration. Here, a method for dynamic micropatterning is reported, where the non-adhesive surface surrounding adhesive micropatterns is rapidly converted to support specific cell-matrix interactions while allowing simultaneous imaging of the cells. The technique is based on ultraviolet photopatterning of biotinylated polyethylene glycol-grafted poly-L-lysine, and it is simple, inexpensive, and compatible with a wide range of streptavidin-conjugated ligands. Experiments using biotinylation-based dynamic micropatterns reveal that distinct extracellular matrix ligands and bivalent integrin-clustering antibodies support different degrees of front-rear polarity in human glioblastoma cells, which correlates to altered directionality and persistence upon release and migration on fibronectin. Unexpectedly, however, neither an asymmetric cell shape nor centrosome orientation can fully predict the future direction of migration. Taken together, biotinylation-based dynamic micropatterns allow easily accessible and highly customizable control over cell morphology and motility.

Melanocortin 1 receptor regulates cholesterol and bile acid metabolism in the liver.

Melanocortin 1 receptor (MC1-R) is widely expressed in melanocytes and leukocytes and is thus strongly implicated in the regulation of skin pigmentation and inflammation. MC1-R has also been found in the rat and human liver, but its functional role has remained elusive. We hypothesized that MC1-R is functionally active in the liver and involved in the regulation of cholesterol and bile acid metabolism. We generated hepatocyte-specific MC1-R knock-out (Mc1r LKO) mice and phenotyped the mouse model for lipid profiles, liver histology, and bile acid levels. Mc1r LKO mice had significantly increased liver weight, which was accompanied by elevated levels of total cholesterol and triglycerides in the liver as well as in the plasma. These mice demonstrated also enhanced liver fibrosis and a disturbance in bile acid metabolism as evidenced by markedly reduced bile acid levels in the plasma and feces. Mechanistically, using HepG2 cells as an in vitro model, we found that selective activation of MC1-R in HepG2 cells reduced cellular cholesterol content and enhanced uptake of low- and high-density lipoprotein particles via a cAMP-independent mechanism. In conclusion, the present results demonstrate that MC1-R signaling in hepatocytes regulates cholesterol and bile acid metabolism and its deficiency leads to hypercholesterolemia and enhanced lipid accumulation and fibrosis in the liver.