Abstract
Apelin-APJ receptor signaling regulates vascular tone in cerebral and peripheral arteries. We recently reported that apelin inhibits BKCa channel function in cerebral arteries, resulting in impaired endothelium-dependent relaxations. In contrast, apelin causes endothelium-dependent relaxation of coronary arteries. However, the effects of apelin on BKCa channel function in coronary arterial myocytes have not yet been explored. We hypothesized that apelin-APJ receptor signaling does not have an inhibitory effect on coronary arterial BKCa channels and hence does not alter nitric oxide (NO)-dependent relaxation of coronary arteries. Patch clamp recording was used to measure whole cell K+ currents in freshly isolated coronary smooth muscle cells. Apelin had no effect on the increases in current density in response to membrane depolarization or to NS1619 (a BKCa channel opener). Moreover, apelin did not inhibit NO/cGMP-dependent relaxations that required activation of BKCa channels in isolated coronary arteries. Apelin-APJ receptor signaling caused a marked increase in intracellular Ca2+ levels in coronary arterial smooth muscle cells, but failed to activate PI3-kinase to increase phosphorylation of Akt protein. Collectively, these data provide mechanistic evidence that apelin has no inhibitory effects on BKCa channel function in coronary arteries. The lack of inhibitory effect on BKCa channels makes it unlikely that activation of APJ receptors in coronary arteries would adversely affect coronary flow by creating a vasoconstrictive environment. It can be expected that apelin or other APJ receptor agonists in development will not interfere with the vasodilator effects of endogenous BKCa channel openers.
Highlights
Apelin is a vasoactive peptide found in many organs and tissues including, for example, adipose tissue (Boucher et al, 2005), atria (Földes et al, 2003), blood vessels (Kleinz and Davenport, 2004), lungs, kidneys, brain (Folino et al, 2015; Yan et al, 2020)
That apelin did not activate the PI3K/Akt-signaling pathway in coronary arterial smooth muscle cells provides a plausible mechanistic explanation as to why APJ receptors may not be efficiently linked to BKCa channels in coronary myocytes; the possibility that another intracellular signaling pathway plays a role in the lack of inhibitory effect of apelin on BKCa channel function cannot be ruled out
The absence of effect of apelin on BKCa channels and PI3 kinase/Akt signaling is not due to an inability to activate APJ receptor signaling in coronary arterial smooth muscle cells, since apelin caused a rapid and robust increase in intracellular Ca2+ levels
Summary
Apelin is a vasoactive peptide found in many organs and tissues including, for example, adipose tissue (Boucher et al, 2005), atria (Földes et al, 2003), blood vessels (Kleinz and Davenport, 2004), lungs, kidneys, brain (Folino et al, 2015; Yan et al, 2020). An increasing body of evidence indicates that the apelin-APJ receptor signaling system regulates vascular function in mammalian arteries and veins (Gurzu et al, 2006; Jia et al, 2007; Salcedo et al, 2007; Wang et al, 2016; Nagano et al, 2019), including those from humans (Katugampola et al, 2001; Kleinz and Davenport, 2004; Maguire et al, 2009; Schinzari et al, 2017). Modulation of BKCa channel activity is a critical mechanism for regulating blood vessel diameter and flow
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