Abstract 15585: Mice Expressing Unphosphorylatable Phospholemman Show an Attenuated Cardiovascular Response to Stress and Beta-Adrenergic Stimulation
Phospholemman (PLM) is expressed in both cardiac and vascular smooth muscle and forms an integral part of the Na/K pump complex. PLM provides the link between kinase activation and Na/K pump modulation. We hypothesise that Na/K pump activation via PLM phosphorylation at 3 cytoplasmic residues plays an important role in Na regulation during the fight or flight response and that unphosphorylatable PLM may thus limit the cardiovascular response to stress. To test this, a novel knock-in mouse (PLM-KI) was generated in which the endogenous allele was globally replaced with one expressing unphosphorylatable PLM (serines 63, 68 and 69 substituted with alanines). Cardiac function in vivo was assessed by echocardiography (n=12–15/grp), pressure-volume catheterization (n=10–12/grp) and, in unanesthetized mice, blood pressure (BP) telemetry (n=6–8/grp). Effects of restraint stress and isoproterenol (ISO: ip 10 mg/kg) were investigated in telemetered mice. At rest, heart rate, blood pressure, echocardiography and PV loops all showed no differences compared to wild type (WT) mice (see selected data in Table). However, in conscious mice, the Low/High frequency ratio of heart rate variability (HRV), indicative of sympatho-vagal tone, was 4-fold lower in PLM-KI vs WT mice. Acute restraint stress for 20min resulted in pressor and tachycardic response in both groups, however this was significantly attenuated in PLM-KI mice. IP injection with the non-selective β-adrenoceptor agonist ISO elicited a sustained tachycardia in both PLM-KI and WT mice however this was again significantly reduced in PLM-KI mice. In conclusion, phosphorylation of PLM, and the associated Na/K pump stimulation, plays a role in the chronotropic and pressor responses to stress. In the conscious PLM-KI mouse (in which PLM is unphosphorylatable) the attenuated response to sympathetic stimulation is associated with a profound and possibly adaptive shift in basal sympathetic/parasympathetic tone.
- © 2010 by American Heart Association, Inc.