Date Published: August 09, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Robert Little, Min Zi, Sally K. Hammad, Loan Nguyen, Alexandra Njegic, Sathishkumar Kurusamy, Sukhpal Prehar, Angel L. Armesilla, Ludwig Neyses, Clare Austin, Elizabeth J. Cartwright.
Hypertension is a well‐established risk factor for adverse cardiovascular events, and older age is a risk factor for the development of hypertension. Genomewide association studies have linked ATP2B1, the gene for the plasma membrane calcium ATPase 1 (PMCA1), to blood pressure (BP) and hypertension. Here, we present the effects of reduction in the expression of PMCA1 on BP and small artery structure and function when combined with advancing age. Heterozygous PMCA1 null mice (PMCA1Ht) were generated and conscious BP was measured at 6 to 18 months of age. Passive and active properties of isolated small mesenteric arteries were examined by pressure myography. PMCA1Ht mice exhibited normal BP at 6 and 9 months of age but developed significantly elevated BP when compared to age‐matched wild‐type controls at ≥12 months of age. Decreased lumen diameter, increased wall thickness and increased wall:lumen ratio were observed in small mesenteric arteries from animals 9 months of age and older, indicative of eutrophic remodelling. Increases in mesenteric artery intrinsic tone and global intracellular calcium were evident in animals at both 6 and 18 months of age. Thus, decreased expression of PMCA1 is associated with increased BP when combined with advancing age. Changes in arterial structure precede the elevation of BP. Pathways involving PMCA1 may be a novel target for BP regulation in the elderly.
Cardiovascular diseases are the world’s leading cause of morbidity and mortality. Hypertension is a major modifiable risk factor for adverse cardiovascular events including stroke and aneurysm, and for heart and renal failure (Kearney et al., 2005). It is thought that at least one in five people worldwide have elevated blood pressure (BP) and that high BP contributes to around 9 million deaths worldwide annually (Mancia et al., 2013; Mozaffarian et al., 2016).
PMCA1Ht and PMCA1flox/flox controls (WT) were born in the predicted ratio given that PMCA1 total knockouts are embryonic lethal (Okunade et al., 2004), with neither male nor female PMCA1Ht mice displaying reduced fertility compared to WT. PMCA1Ht mice were indistinguishable by eye from WT, appeared healthy and appropriately active, and had similar lifespan to WT animals.
This study shows that reduced expression of PMCA1 in mice correlates with elevated BP and small artery remodelling when combined with aging. Importantly, we show that arterial remodelling precedes the development of elevated BP. Thus, we propose that reduced expression of PMCA1 predisposes to the development of elevated BP when combined with aging, suggesting that a PMCA1‐mediated mechanism could be targeted to reduce the burden of high BP in older age.
This work was supported by a programme grant from the Medical Research Council UK (G1002082). S. K. Hammad received financial support from the University of Zagazig and A. Njegic from the British Heart Foundation as a PhD candidates during this project.
The authors declare no conflict of interest.
R. Little, M. Zi, S. Hammad, L. Nguyen, A. Njegic, S. Kurusamy, A. Armesilla, S. Prehar performed the research; R. Little, M. Zi, S. Hammad, A. Njegic analysed the data; C Austin, EJ Cartwright and L Neyses designed the research study; L Neyses, EJ Cartwright and C Austin contributed to acquiring funding; R Little, C Austin and EJ Cartwright contributed to writing the manuscript.