Metformin induction of heat shock factor 1 activation and the mitochondrial unfolded protein response alleviate cardiac remodeling in spontaneously hypertensive rats.

Heart failure and cardiac remodeling are both characterized by mitochondrial dysfunction. Healthy mitochondria are required for adequate contractile activity and appropriate regulation of cell survival. In the mammalian heart, enhancement of the mitochondrial unfolded protein response (UPRmt) is cardioprotective under pressure overload conditions. We explored the UPRmt and the underlying regulatory mechanism in terms of hypertension-induced cardiac remodeling and the cardioprotective effect of metformin. Male spontaneously hypertensive rats and angiotensin II-treated neonatal rat cardiomyocytes were used to induce cardiac hypertrophy. The results showed that hypertension induced the formation of aberrant mitochondria, characterized by a reduced mtDNA/nDNA ratio and swelling, as well as lower levels of mitochondrial complexes I to V and inhibition of the expression of one protein subunit of each of complexes I to IV. Such changes eventually enlarged cardiomyocytes and increased cardiac fibrosis. Metformin treatment increased the mtDNA/nDNA ratio and regulated the UPRmt, as indicated by increased expression of activating transcription factor 5, Lon protease 1, and heat shock protein 60, and decreased expression of C/EBP homologous protein. Thus, metformin improved mitochondrial ultrastructure and function in spontaneously hypertensive rats. In vitro analyses revealed that metformin reduced the high levels of angiotensin II-induced mitochondrial reactive oxygen species in such animals and stimulated nuclear translocation of heat shock factor 1 (HSF1). Moreover, HSF1 small-interfering RNA reduced the metformin-mediated improvements in mitochondrial morphology and the UPRmt by suppressing hypertrophic signals and cardiomyocyte apoptosis. These results suggest that HSF1/UPRmt signaling contributes to the beneficial effects of metformin. Metformin-mediated targeting of mitochondrial protein homeostasis and modulation of HSF1 levels have potential therapeutic implications in terms of cardiac remodeling.

Activation of the M3AChR and Notch1/HSF1 Signaling Pathway by Choline Alleviates Angiotensin II-Induced Cardiomyocyte Apoptosis.

Angiotensin II- (Ang II-) induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Choline exerts cardioprotective effects; however, its effects on Ang II-induced cardiomyocyte apoptosis are unclear. In this study, the role and underlying mechanism of choline in regulating Ang II-induced cardiomyocyte apoptosis were investigated using a model of cardiomyocyte apoptosis, which was induced by exposing neonatal rat cardiomyocytes to Ang II (10-6 M, 48 h). Choline promoted heat shock transcription factor 1 (HSF1) nuclear translocation and the intracellular domain of Notch1 (NICD) expression. Consequently, choline attenuated Ang II-induced increases in mitochondrial reactive oxygen species (mtROS) and promotion of proapoptotic protein release from mitochondria, including cytochrome c, Omi/high-temperature requirement protein A2, and second mitochondrial activator of caspases/direct inhibitor of apoptosis-binding protein with low P. The reversion of these events attenuated Ang II-induced increases in cardiomyocyte size and numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells, presumably via type 3 muscarinic acetylcholine receptor (M3AChR). Indeed, downregulation of M3AChR or Notch1 blocked choline-mediated upregulation of NICD and nuclear HSF1 expression, as well as inhibited mitochondrial apoptosis pathway and cardiomyocyte apoptosis, indicating that M3AChR and Notch1/HSF1 activation confer the protective effects of choline. In vivo studies were performed in parallel, in which rats were infused with Ang II for 4 weeks to induce cardiac apoptosis. The results showed that choline alleviated cardiac remodeling and apoptosis of Ang II-infused rats in a manner related to activation of the Notch1/HSF1 pathway, consistent with the in vitro findings. Taken together, our results reveal that choline impedes oxidative damage and cardiomyocyte apoptosis by activating M3AChR and Notch1/HSF1 antioxidant signaling, and suggest a novel role for the Notch1/HSF1 signaling pathway in the modulation of cardiomyocyte apoptosis.

Preparation of Maleic Anhydride Grafted Polybutene and Its Application in Isotactic Polybutene-1/Microcrystalline Cellulose Composites.

Microcrystalline cellulose (MCC) offers great potential to improve the mechanical and crystallization properties of isotactic polybutene-1 (iPB) because of its low cost, biodegradability, renewability and excellent mechanical properties. However, the compatibility of polar MCC and non-polar iPB is poor. In this study, maleic anhydride grafted polybutene (MAPB) was prepared by the solution method and was used as a compatibilizer in the fabrication of iPB/MCC composites by using a twin screw extruder. The ultimate tensile strength, tensile modulus, flexural strength, flexural modulus of the iPB/MCC composites increased by 3.1%, 16.5%, 10.7%, 6.5%, respectively, compared with that of pure iPB. With MAPB addition, these values increased by 17.2%, 31%, 17.5% and 10%, respectively, compared with that of pure iPB. The heat-distortion temperature and thermal-decomposition temperature of all composites increased with an increased MCC content. The non-isothermal crystallization of the iPB/MCC composites shows that MCC addition can promote iPB crystallization, because the non-isothermal crystallization curve of the composites moves toward a higher temperature, especially after MAPB addition. Scanning electron micrographs indicate that the compatibility of the iPB/MCC has been enhanced significantly.

Isothermal Crystallization and Rheology Properties of Isotactic Polypropylene/Bacterial Cellulose Composite.

Bacterial cellulose (BC) is a new kind of cellulose with great potential in enhancing preparation of isotactic Polypropylene (iPP) composites, which have been found with excellent performance. However, the interface compatibility between BC and iPP is poor. In this study, iPP/BC composites were prepared by solution mixing. Esterification modified BC (CO) and Maleic anhydride grafted polypropylene (MAPP) added as a compatibilizer was both used to improve the interfacial compatibility of the iPP/BC composites. The rheology and isothermal crystallization behavior of the composites was tested and discussed. The result shows that the complex viscosity and storage modulus of the composite significantly increase in the rule iPP, iPP/BC2, iPP/CO2, and M-iPP/BC3, which indicates that the compatibility of the composite increases as this rule. According to the isothermal crystallization kinetics result, the crystal growth mode of iPP was not affected by the addition of BC and the interfacial compatibility. The spherulite growth rate of the iPP/BC composite increases with increasing crystallization temperature. Especially, the value decreases as the same rule with the complex viscosity and storage modulus of the composite at the same isothermal crystallization temperature. These results suggest that the interface compatibility of iPP/BC composites is greatly improved and the interface compatibility of the M-iPP/BC3 is better than the iPP/CO2.