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

Poster Board Number: E84

Sushil Mahata (VA San Diego Healthcare System, VA San Diego Healthcare System), Matthew Liu (University of California San Diego), Suborno Jati (University of California San Diego), Kechun Tang (VA San Diego Healthcare System), Geert Bogaart (University of Groningen, University of Groningen), Gourisankar Ghosh (University of California San Diego)

Objective: Aging is a public health, societal, and economic problem around the world. Adults aged 65 years and older are the fastest growing segment of the US population, and their number is expected to double to 89 million by 2050. Two physiological processes that are more prevalent in older populations are hypertension and diabetes. Chromogranin A (protein: CgA; mouse gene: Chga) knockout (Chga-KO) mice are associated with hypertension but also protected against developing autoimmune diabetes; however, the effect of these phenotypes on mice as they age including mortality remains unclear, as does a possible mechanism for developing both phenotypes. This study examined the long-term effects of aging in Chga-KO mice and sought to elucidate a possible mechanism for both hypertension and diabetes by focusing on the inflammatory pathway.

Methods and

Results: Chga-KO mice display two opposite aging phenotypes: hypertension but heightened insulin sensitivity. We determined these phenotypes in aging CgA mice by measuring blood pressure and blood glucose. 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-a, IFN-g and CCL2 and increased mitochondrial fission, these phenotypes were the opposite in aging Chga-KO mice. Chga-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 Chga-KO mice spontaneously reversed with aging. Supplementation of Chga-KO mice with pancreastatin (human CgA273-301), a hyperglycemic peptide produced from CgA by proteolysis, increased both blood glucose levels and blood pressure, implicating hyperglycemia, and hypertension.

Conclusions: We conclude that age-related insulin resistance and hypertension are caused in part by CgA.

Department of Veterans Affairs (I01 BX003934 to SKM).