Multi-tasking RGS proteins in the heart: the next therapeutic target?

Regulator of G-protein-signaling (RGS) proteins play a key role in the regulation of G-protein-coupled receptor (GPCR) signaling. The characteristic hallmark of RGS proteins is a conserved approximately 120-aa RGS region that confers on these proteins the ability to serve as GTPase-activating proteins (GAPs) for G(alpha) proteins. Most RGS proteins can serve as GAPs for multiple isoforms of G(alpha) and therefore have the potential to influence many cellular signaling pathways. However, RGS proteins can be highly regulated and can demonstrate extreme specificity for a particular signaling pathway. RGS proteins can be regulated by altering their GAP activity or subcellular localization; such regulation is achieved by phosphorylation, palmitoylation, and interaction with protein and lipid-binding partners. Many RGS proteins have GAP-independent functions that influence GPCR and non-GPCR-mediated signaling, such as effector regulation or action as an effector. Hence, RGS proteins should be considered multifunctional signaling regulators. GPCR-mediated signaling is critical for normal function in the cardiovascular system and is currently the primary target for the pharmacological treatment of disease. Alterations in RGS protein levels, in particular RGS2 and RGS4, produce cardiovascular phenotypes. Thus, because of the importance of GPCR-signaling pathways and the profound influence of RGS proteins on these pathways, RGS proteins are regulators of cardiovascular physiology and potentially novel drug targets as well.

Disruption of protein kinase A interaction with A-kinase-anchoring proteins in the heart in vivo: effects on cardiac contractility, protein kinase A phosphorylation, and troponin I proteolysis.

Protein kinase A (PKA)-dependent phosphorylation is regulated by targeting of PKA to its substrate as a result of binding of regulatory subunit, R, to A-kinase-anchoring proteins (AKAPs). We investigated the effects of disrupting PKA targeting to AKAPs in the heart by expressing the 24-amino acid regulatory subunit RII-binding peptide, Ht31, its inactive analog, Ht31P, or enhanced green fluorescent protein by adenoviral gene transfer into rat hearts in vivo. Ht31 expression resulted in loss of the striated staining pattern of type II PKA (RII), indicating loss of PKA from binding sites on endogenous AKAPs. In the absence of isoproterenol stimulation, Ht31-expressing hearts had decreased +dP/dtmax and -dP/dtmin but no change in left ventricular ejection fraction or stroke volume and decreased end diastolic pressure versus controls. This suggests that cardiac output is unchanged despite decreased +dP/dt and -dP/dt. There was also no difference in PKA phosphorylation of cardiac troponin I (cTnI), phospholamban, or ryanodine receptor (RyR2). Upon isoproterenol infusion, +dP/dtmax and -dP/dtmin did not differ between Ht31 hearts and controls. At higher doses of isoproterenol, left ventricular ejection fraction and stroke volume increased versus isoproterenol-stimulated controls. This occurred in the context of decreased PKA phosphorylation of cTnI, RyR2, and phospholamban versus controls. We previously showed that expression of N-terminal-cleaved cTnI (cTnI-ND) in transgenic mice improves cardiac function. Increased cTnI N-terminal truncation was also observed in Ht31-expressing hearts versus controls. Increased cTnI-ND may help compensate for reduced PKA phosphorylation as occurs in heart failure.

Randomized Trial of Telephone Intervention in Chronic Heart Failure (DIAL): study design and preliminary observations.

BACKGROUND: In the last few years different approaches based on comprehensive patient care and close surveillance by multidisciplinary teams have shown promising results in heart failure. However, current evidence mainly derives from small and often nonrandomized studies performed at a single center, with selected populations, using dissimilar and complex strategies. We designed a large randomized study to test the hypothesis that a single program, based on a centralized telephone intervention performed by trained nurses, could reduce morbidity and mortality in chronic heart failure. METHODS: The Randomized Trial of Telephone Intervention in Chronic Heart Failure (DIAL) is a randomized, controlled, open trial designed to compare frequent telephone follow-up intervention versus control. We enrolled 1518 patients with stable chronic heart failure and optimal treatment from 51 centers in Argentina. DIAL trial intervention strategy is based on frequent telephone follow-up provided by nurses trained in heart failure and performed from a single surveillance center, assuring a homogeneous and high quality intervention. The primary objective is to determine the effect of the intervention as compared with the usual follow-up on the combined endpoint of all-cause mortality or hospitalization for worsening heart failure. The objectives of the intervention are education, counseling, and monitoring to enhance self-control mechanisms, timely medical visits, diet, and drug therapy compliance. Telephone call frequency was determined according to preestablished criteria of clinical status severity assessed at each phone contact. The study ended in August 2002. CONCLUSION: The results of this study may provide information about mortality, hospitalizations, and quality of life contributing to set standards for management programs in the current treatment of chronic heart failure.