Increased Blood Pressure and Hyperdynamic Cardiovascular Responses in Carriers of a Common Hyperfunctional Variant of Adenylyl Cyclase 6

Abstract

Adenylyl cyclase (ADCY) is a critical regulator of metabolic and cardiovascular function. We have identified a genetic variant (A674S) in ADCY isoform 6 (ADCY6). Subsequent studies demonstrated that the expression of this ADCY6 variant paralleled an increase in adenylyl cyclase-mediated functions. However, the impact of this hyperfunctional variant on cardiovascular function is unknown. Therefore, we evaluated the hemodynamic profile of carriers of ADCY6 A674S. The association of ADCY6 A674S with anthropometric and hemodynamic parameters was assessed in 364 healthy white subjects. The allele encoding this variant was present in 6.9% of the subjects, and those individuals had increased blood pressure. To determine the hemodynamic basis for increased blood pressure in carriers of ADCY6 A674S, we assessed forearm blood flow (FBF) and cardiac output at rest, during handgrip exercise (to test vasodilator responsiveness), and with lower body negative pressure [to test forearm vasoconstrictor and heart rate (HR) responsiveness] in a subsample of 21 subjects. At rest, cardiac output and blood pressure were higher in carriers of ADCY6 A674S. This was paralleled by an increase in plasma renin activity, but not in plasma norepinephrine. During handgrip exercise, FBF and vasodilator responses were greater in carriers of ADCY6 A674S. Responses to reactive hyperemia were not different between genotypes. With lower body negative pressure, the HR response to this orthostatic stress was markedly higher in carriers of ADCY6 A674S. These data indicate that the relatively common hyperfunctional ADCY6 A674S variant underlies a hyperdynamic cardiovascular response and increased blood pressure.

Choreographing the adenylyl cyclase signalosome: sorting out the partners and the steps

“…These cellular indices of enhanced adenylyl cyclase function based on expression of this variant paralleled increased potency of ß-adrenergic receptor-mediated vasodilation (Gros et al 2007). Hemodynamically, younger healthy subjects expressing the variant demonstrated increased systolic blood pressure, heart rate, cardiac output, and increased plasma rennin activity (Hodges et al 2010). This phenotype supports the hypothesis that physiological regulation of a specific isoform (AC6) results in the expression of a hyperkinetic hemodynamic phenotype.…”

G-Protein Estrogen Receptor as a Regulator of Low-Density Lipoprotein Cholesterol Metabolism

“…To validate our findings, we examine a London, Ontario-based population of healthy women (n=339). 18 We found that in both population samples, the hypofunctional GPER P16L variant was associated with increased LDL concentrations in women, following a recessive model. Furthermore, in cellular studies, we demonstrate that G1 agonist activation of GPER in HepG2 cells, which endogenously express GPER, 19,20 leads to reduced PCSK9 expression and increased LDL receptor expression.…”

Methamphetamine and HIV-Tat alter murine cardiac DNA methylation and gene expression

“…On that basis, we analyzed gene expression of ADCY6, CACNA1C, MYBPC3, and PGC-1α in relation to METH-induced changes, and Bcl-XL and COX10 in relation to Tat-induced changes. ADCY6 is an adenylate cyclase that mediates β-adrenergic stimulation (Hodges, 2010); Bcl-XL is an antiapoptotic protein; CACNA1C is the L-type calcium channel important for proper cardiac action potentials (Goonasekera, 2012); COX10 is a subunit of mitochondrial Complex 4; MYBPC3 is a myosin binding protein exclusively expressed in the heart and implicated in familial-inherited CM (Adalsteinsdottir, 2014); and PGC-1α is a key activator of mitochondrial biogenesis (Spiegelman, 2007). METH increased gene expression in ADYC6, CACNA1C, MYBPC3, and PGC-1α genes (Figures 6A–D, respectively).…”