The rheological properties of red blood cells (RBCs) play an important role in their microcirculation. RBCs can elastically deform in response to mechanical forces to pass through narrow vessels for effective gas exchange in peripheral tissues. Decreased RBC deformability is observed in lifestyle-related diseases such as diabetes mellitus, hypercholesterolemia, and hypertension, which are pathological conditions linked to increased oxidative stress and decreased nitric oxide (NO) bioavailability. Redox-sensitive cysteine residues on RBC cytoskeletal proteins, such as α- and β-spectrins, responsible for membrane flexibility, are affected by prolonged oxidative stress, leading to reversible and irreversible oxidative modifications and decreased RBC deformability. However, endogenously, and exogenously generated NO protects RBC membrane flexibility from further oxidative modification by shielding redox-sensitive cysteine residues with a glutathione cap. Recent studies have shown that nitrate-rich diets and moderate exercise can enhance NO production to increase RBC deformability by increasing the interplay between RBCs and vascular endothelium-mediated NO bioavailability for microcirculation. This review focuses on the molecular mechanism of RBC- and non-RBC-mediated NO generation, and how diet- and exercise-derived NO exert prophylactic effects against decreased RBC deformability in lifestyle-related diseases with vascular endothelial dysfunction.

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. Endothelial dysfunction caused by hepatic lipotoxicity is an underlying NASH pathology observed in the liver and the cardiovascular system. Here, we evaluated the effect of dietary nitrite on a rat NASH model. Stroke-prone, spontaneously hypertensive 5/Dmcr rats were fed a high-fat/high-cholesterol diet to develop the NASH model, with nitrite or captopril (100 mg/L, each) supplementation in drinking water for 8 weeks. The effects of nitrite and captopril were evaluated using immunohistochemical analyses of the liver and heart tissues. Dietary nitrite suppressed liver fibrosis in the rats by reducing oxidative stress, as measured using the protein levels of nicotinamide adenine dinucleotide phosphate oxidase components and inflammatory cell accumulation in the liver. Nitrite lowered the blood pressure in hypertensive NASH rats and suppressed left ventricular chamber enlargement. Similar therapeutic effects were observed in a captopril-treated rat NASH model, suggesting the possibility of a common signaling pathway through which nitrite and captopril improve NASH pathology. In conclusion, dietary nitrite attenuates the development of NASH with cardiovascular involvement in rats and provides an alternative NASH therapeutic strategy.

Sarcopenia, characterized by skeletal muscle atrophy, was previously considered age-related; however, it is also associated with other diseases. Nonalcoholic fatty liver disease (NAFLD) is known to cause sarcopenia, and its complications have been reported to affect prognosis. The intestinal microbiota of patients with NAFLD or sarcopenia has been found to be altered compared to that of healthy individuals. However, the alterations that occur when both diseases coexist in humans or experimental animals remain unclear. Therefore, this study aimed to determine the intestinal microbiota changes associated with NAFLD with sarcopenia in SHRSP5/Dmcr rats at the time of concomitant disease. Fecal samples were collected from the rectum of SHRSP5/Dmcr rats fed a normal diet (non-NAFLD and non-Sarcopenia, n = 5) or a high-fat and high-cholesterol diet (NAFLD and Sarcopenia, n = 5) for 20 weeks, and subjected to 16S rRNA analysis. In the NAFLD and sarcopenia group, the diversity of the intestinal microbiota was reduced; further, the bacterial species reported in patients with NAFLD or sarcopenia were also changed. At the family level, the abundances of Akkermansiaceae, Bacteroidaceae, and Tannerellaceae were significantly higher whereas Ruminococcaceae and Lactobacillaceae were decreased in the NAFLD and sarcopenia group. At the genus level, the abundances of Akkermansia , Bacteroides , Ruminococcus , and Parabacteroides were significantly higher whereas the abundance of Lactobacillus was significantly decreased in the NAFLD and sarcopenia group. Overall, these findings help improve the existing understanding regarding the intestinal microbiota changes observed in conditions where NASH and sarcopenia co-occur.