The murine PACAP gene (Adcyap1) and its critical role in metabolism and cardiovascular function
Date
2018-11-15
Authors
Cummings, Kevin James
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Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a hormone of considerable interest because of its strongly conserved structure throughout evolution as well as its widespread distribution throughout the nervous system. The purpose of this study was (1) to isolate and characterize the PACAP gene and novel mRNA transcripts and (2) to obtain information regarding its functional importance through the use of a mouse line deficient in PACAP, created in the course of this study by removing the native allele in embryonic stem cells.
In this study, it was discovered that the PACAP protein and gene in mice is of similar structure to the forms identified in other species. Transcripts with differential splicing and alternative transcription initiation sites are present, indicating a high degree of regulation of tissue-specific PACAP production at the transcriptional, and possibly post-transcriptional levels. Much of the variation in transcripts occurs in the 5′UTR.
In addition, it was found that removing the PACAP gene has lethal consequences for mice, with a high proportion of PACAP knockout (PACAP−/− ) animals dying before weaning, in either a sudden-death or wasting fashion, with marked alterations in glucose and fat metabolism, including hypoglycemia, high serum triglycerides and ketone bodies. Also, some PACAP −/− pups showed significant hyperinsulinemia, as well as high levels of IL-6 in their serum. It is speculated that PACAP −/− mice have a defect in insulin sensitivity in the tissues or in glucose sensing at the level of the pancreas, although a defect in lipid metabolism directly cannot be discounted. Whether the defect is primary from loss of PACAP or is due to secondary, downstream effects on the production of other hormones is unknown.
Wild-type mouse cardiac myocytes respond directly to PACAP treatment by significantly increasing both rate and degree of cellular contraction. Furthermore, microarray analysis of wild-type murine cardiac myocytes treated with PACAP revealed the up-regulation of various genes, including genes playing a role in heart inflammation and blood clotting. As well, the p53 gene appears to be down-regulated, implying a role for PACAP in the balance between cell survival and cell death within the heart. An analysis of in vivo cardiovascular function revealed that PACAP−/− animals had deficiencies in both heart rate and breathing during hypothermic challenge. PACAP−/− animals had a faster heart rate at normothermic body temperatures, but had a slower heart rate when challenged with hypothermia. In addition, respiratory arrest occurred in some individuals, and evidence of cardiac ischemia is present in PACAP−/− electrocardiographs.
This study provides evidence that PACAP plays an important role in mammalian metabolism and cardiovascular function, particularly during hypothermic stress. Thus, this study provides more evidence that PACAP may act directly as a stress-response hormone, and future research examining its role in these two systems is certainly warranted.
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Keywords
Endocrine genetics, Hormones, Physiological effect