Effects of a Global Rab27a Null Mutation on Murine PVAT and Cardiovascular Function
Ashley Soucy1,2, Christian Potts1, Abigail Kaija1
1MaineHealth Institute for Research, MaineHealth, Scarborough, ME (A.S., C.P., A.K., A.H., M.M., B.T., J.S., I.P., C.V., L.R., L.L.).
Background:
RAB27A is a member of the RAS oncogene superfamily of GTPases and regulates cell secretory function. It, is expressed within blood vessels and perivascular adipose tissue. We hypothesized that loss of RAB27A would alter cardiovascular function.
Methods:
Body weight of Rab27aash mice was measured from 2 to 18 months of age, along with glucose resorption at 6 and 12 months of age and glucose sensitivity at 18 months of age. Body weight and cellular and molecular features of perivascular adipose tissue and aortic tissue were examined in a novel C57BL/6J Rab27a null strain. Analyses included morphometric quantification and proteomic analyses. Wire myography measured vasoreactivity, and echocardiography measured cardiac function. Comparisons across ages and genotypes were evaluated via 2-way ANOVA with multiple comparison testing. Significance for myography was determined via 4-parameter nonlinear regression testing.
Results:
Genome-wide association data linked rare human RAB27A variants with body mass index and glucose handling. Changes in glucose tolerance were observed in Rab27aash male mice at 18 months of age. In WT (wild-type) and Rab27a null male mice, body weight, adipocyte lipid area, and aortic area increased with age. In female mice, only body weight increased with age, independent of RAB27A presence. Protein signatures from male Rab27a null mice suggested greater associations with cardiovascular and metabolic phenotypes compared with female tissues. Wire myography results showed Rab27a null males exhibited increased vasoconstriction and reduced vasodilation at 8 weeks of age. Rab27a null females exhibited increased vasoconstriction and vasodilation at 20 weeks of age. Consistent with these vascular changes, male Rab27a null mice experienced age-related cardiomyopathy, with severe differences observed by 21 weeks of age.
Conclusions:
Global RAB27A loss impacted perivascular adipose tissue and thoracic aorta proteomic signatures, altered vasocontractile responses, and decreased left ventricular ejection fraction in mice.
Insights
Loss of RAB27A in mice altered cardiovascular function, impacting perivascular adipose tissue and aorta. This study reveals RAB27A
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- GTPase Signaling Pathways
Background:
- RAB27A, a GTPase regulating secretion, is expressed in blood vessels and perivascular adipose tissue.
- Its role in cardiovascular function is not well understood.
- This study investigates the impact of RAB27A loss on cardiovascular health.
Purpose of the Study:
- To determine how RAB27A deficiency affects cardiovascular and metabolic functions.
- To analyze the cellular and molecular changes in perivascular adipose tissue and aorta upon RAB27A loss.
- To assess the impact on vasoreactivity and cardiac function in a mouse model.
Main Methods:
- Generation and characterization of a RAB27A-null mouse strain.
- Assessment of body weight, glucose tolerance, and sensitivity.
- Proteomic analysis of perivascular adipose and aortic tissues.
- Wire myography for vasoreactivity and echocardiography for cardiac function.
Main Results:
- RAB27A deficiency altered glucose handling in male mice and increased body weight, adipocyte lipid area, and aortic area with age.
- Proteomic analysis indicated RAB27A loss impacts cardiovascular and metabolic phenotypes, particularly in males.
- Vascular responses and cardiac function were significantly impaired in RAB27A-null male mice, showing age-related cardiomyopathy.
Conclusions:
- Global RAB27A loss significantly impacts perivascular adipose tissue and thoracic aorta.
- Loss of RAB27A alters vasocontractile responses and cardiac function, specifically decreasing left ventricular ejection fraction.
- These findings highlight RAB27A's critical role in maintaining cardiovascular homeostasis.
