Biology subjects

Liu, M. A.

Publications and source records attributed to Liu, M. A..

2 recordsLinked to original sources

bioRxiv2021

Chromogranin A plays a crucial role in the age-related development of insulin resistance and hypertension

Aging is associated with the development of metabolic disorders, including insulin resistance and hypertension. Young mice that are negative for the neuroendocrine prohormone Chromogranin A (CgA knockout, CgA-KO) display two opposite aging phenotypes: hypertension but heightened insulin sensitivity. We determined these phenotypes in aging CgA mice. In comparison, aging wild-type (WT) mice gradually lost glucose tolerance and insulin sensitivity. Moreover, while aging WT mice had increased inflammation with higher plasma TNF-, IFN-{gamma} and CCL2 and increased mitochondrial fission, these phenotypes were the opposite in aging CgA-KO mice. CgA-KO mice also showed increased expression of mitochondrial and nuclear-encoded complex I genes, implying that they were healthier than WT mice. Most intriguingly, the hypertension in CgA-KO mice was spontaneously reversed with aging. Supplementation of CgA-KO mice with pancreastatin, a hyperglycemic peptide produced from CgA by proteolysis, increased both blood glucose levels and blood pressure, implicating hyperglycemia, and hypertension. We conclude that age-related insulin resistance and hypertension are caused by CgA.

physiology↗

bioRxiv2020

Catestatin (CST) is a key mediator of the immunoendocrine regulation of cardiovascular function

Hypertension (HTN) is associated with inflammation and excessive production of catecholamines. Hypertensive patients have reduced plasma levels of Catestatin (CST), a bioactive cleavage product of the prohormone Chromogranin A (CgA). In mouse models, HTN symptoms can be reduced by administration of CST, but the role of CST in the regulation of cardiovascular function is unknown. In this study, we generated mice with knockout (KO) of the region of the CgA gene coding for CST (CST-KO) and found that CST-KO mice are not only hypertensive as predicted, but also display left ventricular hypertrophy, have marked macrophage infiltration of the heart and adrenal gland, and have elevated levels of pro-inflammatory cytokines and catecholamines. Intraperitoneal injection with CST reversed these phenotypes, and ischemic pre-conditioning-induced cardioprotection was also abolished in CST-KO mice. Experiments with chlodronate depletion of macrophages and bone-marrow transfer showed that macrophages produce CST and that the anti-hypertensive effects of CST are mediated in part via CSTs immunosuppression of macrophages as a form of feedback inhibition. The data thus implicate CST as a key autocrine attenuator of the cardiac inflammation in HTN by reducing macrophage inflammation.

physiology↗