1 research outputs found
Enhanced Heart Failure in RedoxāDead Cys17Ser PKARIĪ± KnockāIn Mice
Background
PKARIĪ± (protein kinase A type IāĪ± regulatory subunit) is redoxāactive independent of its physiologic agonist cAMP. However, it is unknown whether this alternative mechanism of PKARIĪ± activation may be of relevance to cardiac excitationācontraction coupling.
Methods and Results
We used a redoxādead transgenic mouse model with homozygous knockāin replacement of redoxāsensitive cysteine 17 with serine within the regulatory subunits of PKARIĪ± (KI). Reactive oxygen species were acutely evoked by exposure of isolated cardiac myocytes to AngII (angiotensin II, 1 Āµmol/L). The longāterm relevance of oxidized PKARIĪ± was investigated in KI mice and their wildātype (WT) littermates following transverse aortic constriction (TAC). AngII increased reactive oxygen species in both groups but with RIĪ± dimer formation in WT only. AngII induced translocation of PKARI to the cell membrane and resulted in protein kinase Aādependent stimulation of ICa (Lātype Ca current) in WT with no effect in KI myocytes. Consequently, Ca transients were reduced in KI myocytes as compared with WT cells following acute AngII exposure. Transverse aortic constrictionārelated reactive oxygen species formation resulted in RIĪ± oxidation in WT but not in KI mice. Within 6 weeks after TAC, KI mice showed an enhanced deterioration of contractile function and impaired survival compared with WT. In accordance, compared with WT, ventricular myocytes from failing KI mice displayed significantly reduced Ca transient amplitudes and lack of ICa stimulation. Conversely, direct pharmacological stimulation of ICa using Bay K8644 rescued Ca transients in AngIIātreated KI myocytes and contractile function in failing KI mice in vivo.
Conclusions
Oxidative activation of PKARIĪ± with subsequent stimulation of ICa preserves cardiac function in the setting of acute and chronic oxidative stress