Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension

Abstract

The incidence of hypertension, the major modifiable risk factor for cardiovascular disease, is increasing. Thus, there is a pressing need for the development of new and more effective strategies to prevent and treat hypertension. Development of these relies on a continued evolution of our understanding of the mechanisms which control blood pressure (BP). Resistance arteries are important in the regulation of total peripheral resistance and BP; changes in their structure and function are strongly associated with hypertension. Anti-hypertensives which both reduce BP and reverse changes in resistance arterial structure reduce cardiovascular risk more than therapies which reduce BP alone. Hence, identification of novel potential vascular targets which modify BP is important. Hypertension is a multifactorial disorder which may include a genetic component. Genome wide association studies have identified ATP2B1, encoding the calcium pump plasma membrane calcium ATPase 1 (PMCA1), as having a strong association with BP and hypertension. Knockdown or reduced PMCA1 expression in mice has confirmed a physiological role for PMCA1 in BP and resistance arterial regulation. Altered expression or inhibition of PMCA4 has also been shown to modulate these parameters. The mechanisms whereby PMCA1 and 4 can modulate vascular function remain to be fully elucidated but may involve regulation of intracellular calcium homeostasis and/or comprise a structural role. However, clear physiological links between PMCA and BP, coupled with experimental studies directly linking PMCA1 and 4 to changes in BP and arterial function, suggest that they may be important targets for the development of new pharmacological modulators of BP.

ATP2B1 gene Silencing Increases Insulin Sensitivity through Facilitating Akt Activation via the Ca2+/calmodulin Signaling Pathway and Ca2+-associated eNOS Activation in Endothelial Cells

“…Since then, strong associations between the ATP2B1 gene loci and blood pressure or hypertension have also been reported in different ethnic groups 13 , 14 , 18 . Additionally, SNPs related to ATP2B1 gene have been found to be genetically associated with pulse pressure, coronary artery disease and coronary artery calcification and myocardial infarction in chronic kidney disease 19 . These genetic studies in large populations indicate that the ATP2B1 gene has pleiotropic effects on the cardiovascular system.…”

“…Because of the association of the ATP2B1 gene with hyperlipidemia and diabetes, it is hypothesized that indirect effects of the ATP2B1 gene on metabolism may play a potential role in regulating cardiovascular function 18 . Evidence from experimental studies shows that increase in blood pressure induced by ATP2B1 gene knockdown may be due to impaired endothelium-dependent relaxation, increased contractility of mesenteric arteries, or elevated phenylephrine-induced vasoconstriction 19 . In our current study, ATP2B1 gene silencing led to increased insulin-induced Akt activation in endothelial cells that were cultured in vitro .…”

“…The ATP2B1 gene, located on chromosome 12q21.33, encodes Plasma Membrane Calcium ATPase 1 (PMCA1) 19 . In addition, it is well known that PMCA1 protein plays a crucial role in the maintenance of intracellular Ca 2+ homeostasis by ejecting Ca 2+ ions from the cytosol 20 .…”

The Plasma Membrane Calcium ATPasesand Their Role as Major New Players in Human Disease

“…As described in section IIIA, PMCA1 has been identified in numerous studies as a leading candidate gene for the development of hypertension. It is perhaps not surprising therefore that both PMCA1 and 4 have been shown to influence vascular tone (129,141,187,333,343) and that they have been identified as potential targets for the treatment of essential hypertension (214).…”

Reduced expression of PMCA1 is associated with increased blood pressure with age which is preceded by remodelling of resistance arteries

“…Whilst this indicates that PMCA1 may play some role in increased vascular resistance, there is a wealth of evidence to support the importance of structural changes of resistance arteries in hypertension (Rizzoni et al ., ; Heagerty et al ., ). Rearrangement of vascular smooth muscle cells (VSMCs) around a smaller lumen diameter without any global change in the arterial wall cross‐sectional area, termed eutrophic inward remodelling, has been shown to be a conventional small artery structural abnormality in patients with chronic essential hypertension (Mulvany & Aalkjaer, ; Rizzoni et al ., ; Heagerty et al ., ; Little et al ., ). Such changes in small artery structure have strong prognostic significance in hypertensive patients, over and above all other known cardiovascular risk factors (Rizzoni et al ., ; Mathiassen et al ., ).…”