Chromogranin A Knockout Mice Have Spontaneous Reversal of Hypertensive and Insulin Resistant Phenotypes as They Age (>1yr)

Abstract

Objective Both diabetes and hypertension are two of the leading risk factors for mortality and morbidity worldwide, and both have seen marked increases in prevalence in the last few decades. Chromogranin A (human: CHGA; mouse: Chga) is often known as a neuroendocrine peptide and tumor marker, but recent evidence has found that 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 in Chga-KO mice and also sought to elucidate a possible mechanism for both hypertension and diabetes by focusing on the inflammatory pathway. Methods and Results Compared to wild-type (WT), Chga-KO mice demonstrate initial hypertension with a systolic blood pressure (SBP) of 115.7±3.15 in Chga-KO vs 106±1.539 in WT mice (p<0.007) at 0.5 years of age. The SBP decreases with age to 109.2±1.82 vs 110.7±1.13 in WT mice (p=0.43) at 1 year and a SBP of 93.83±1.47 in Chga-KO mice vs 115.8±1.02 in WT mice at 2 years of age (p<0.001). Similarly, while WT mice demonstrate the classic decrease in glucose tolerance and insulin sensitivity as they age, Chga-KO mice have the opposite with a marked improvement in blood glucose tolerance and sensitivity to insulin. Additionally, although the exact relationship remains unclear, as WT mice age, they generally demonstrate increased levels of inflammation compared to Chga-KO mice at all ages (increased proinflammatory cytokine TNF-a, and decreased anti-inflammatory cytokine IL-10) with the greatest differences at older ages. Conclusions Together, these results suggest that Chga-KO, which is known to cause hypertension in mice does not increase mortality, and that mice instead have improved long-term outcomes when considering blood pressure and diabetes. Furthermore, although it cannot be proven yet, there does seem to be a relationship between lower BP, diabetes and anti-inflammation.