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Myocardial β-adrenergic receptor downregulation in heart failure☆

Nos anos 1980 assistiu‐se a uma evolução profunda do conhecimento sobre a fisiopatologia da insuficiência cardíaca (IC): outrora considerada uma síndrome clínica de origem fundamentalmente estrutural, a IC começou a ser vista como a consequência de um desequilíbrio de forças hormonais opostas. Foi, de facto, nesta década que surgiram os estudos basilares sobre o impacto dos sistemas neuro‐hormonais na IC. E destes destacam‐se oito: quatro de natureza vasoconstritora e antinatriurética (o sistema nervoso simpático [SNS], o sistema da renina‐angiotensina‐aldosterona [SRAA], o sistema da vasopressina arginina e a endotelina) e quatro de natureza vasodilatadora e natriurética (o sistema das protaglandinas [PGs], do óxido nítrico [NO], o sistema dopaminérgico e o sistema dos péptidos natriuréticos [NPS]). Fortemente interligados entre si e com um sistema de regulação intrincado, estes sistemas funcionam habitualmente numa homeostasia delicada, cuja disrupção é sinal característico da IC. Nesta revisão é explorado o desenvolvimento histórico do conhecimento sobre o impacto destes sistemas neuro‐hormonais na IC desde os seus primeiros estudos até ao conhecimento atual. Para além disso, são também revisitadas as oportunidades terapêuticas que cada um deles apresenta, bem como as famílias de antagonistas neuro‐hormonais atualmente utilizadas na terapia da IC. Nesta última parte dá‐se especial destaque ao último fármaco aprovado para utilização em doentes com IC com fração de ejeção reduzida, o sacubitril/valsartan, que combina dois antagonistas e que por isso atua simultaneamente em dois sistemas neuro‐hormonais: o SRAA e o NPS.

Our knowledge of the pathophysiology of heart failure (HF) underwent profound changes during the 1980s. Once thought to be of exclusively structural origin, HF began to be seen as the consequence of hormonal imbalance. A number of seminal studies were published in that decade focusing on the impact of neurohormonal activation in HF. Presently, eight neurohormonal systems are known to have a key role in HF development: four stimulate vasoconstriction and sodium/water retention (the sympathetic nervous system, the renin‐angiotensin‐aldosterone system [RAAS], endothelin, and the vasopressin‐arginine system), while the other four stimulate vasodilation and natriuresis (the prostaglandin system, nitric oxide, the dopaminergic system, and the natriuretic peptide system [NPS]). These systems are strongly interconnected and are subject to intricate regulation, functioning together in a delicate homeostasis. Disruption of this homeostasis is characteristic of HF. This review explores the historical development of knowledge on the impact of the neurohormonal systems on HF pathophysiology, from the first studies to current understanding. In addition, the therapeutic potential of each of these systems is discussed, and currently used neurohormonal antagonists are characterized. Special emphasis is given to the latest drug approved for use in HF with reduced ejection fraction, sacubitril/valsartan. This drug combines two different molecules, acting on two different systems (RAAS and NPS) simultaneously.

The Ca^2 +-responsive phosphatase calcineurin/protein phosphatase 2B dephosphorylates the transcription factor NFATc3. In the myocardium activation of NFATc3 down-regulates the expression of voltage-gated K⁺ (K_v) channels after myocardial infarction (MI). This prolongs action potential duration and increases the probability of arrhythmias. Although recent studies infer that calcineurin is activated by local and transient Ca^2 + signals the molecular mechanism that underlies the process is unclear in ventricular myocytes. Here we test the hypothesis that sequestering of calcineurin to the sarcolemma of ventricular myocytes by the anchoring protein AKAP150 is required for acute activation of NFATc3 and the concomitant down-regulation of K_v channels following MI. Biochemical and cell based measurements resolve that approximately 0.2% of the total calcineurin activity in cardiomyocytes is associated with AKAP150. Electrophysiological analyses establish that formation of this AKAP150–calcineurin signaling dyad is essential for the activation of the phosphatase and the subsequent down-regulation of K_v channel currents following MI. Thus AKAP150-mediated targeting of calcineurin to sarcolemmal micro-domains in ventricular myocytes contributes to the local and acute gene remodeling events that lead to the down-regulation of K_v currents.

Our appreciation of the scope and influence of second messenger signaling has its origins in pioneering work on the cAMP-dependent protein kinase. Also called protein kinase A (PKA), this holoenzyme exists as a tetramer comprised of a regulatory (R) subunit dimer and two catalytic (C) subunits. Upon binding of two molecules of the second messenger cAMP to each R subunit, a conformational change in the PKA holoenzyme occurs to release the C subunits. These active kinases phosphorylate downstream targets to propagate cAMP responsive cell signaling events. This article focuses on the discovery, structure, cellular location and physiological effects of the catalytic subunit alpha of protein kinase A (encoded by the gene PRKACA). We also explore the potential role of this essential gene as a molecular mediator of certain disease states.

Hypertrophy increases the risk of heart failure and arrhythmia. Prevention or reversal of the maladaptive hypertrophic phenotype has thus been proposed to treat heart failure. Chronic β-adrenergic receptor (β-AR) stimulation induces cardiomyocyte hypertrophy by elevating 3′,5′-cyclic adenosine monophosphate (cAMP) levels and activating downstream effectors such protein kinase A (PKA). Conversely, hydrolysis of cAMP by phosphodiesterases (PDEs) spatiotemporally restricts cAMP signaling. Here, we demonstrate that PDE4, but not PDE3, is critical in regulating cardiomyocyte hypertrophy, and may represent a potential target for preventing maladaptive hypertrophy. We identify a sequence within the upstream conserved region 1 of PDE4D, termed UCR1C, as a novel activator of PDE4 long isoforms. UCR1C activates PDE4 in complex with A-kinase anchoring protein (AKAP)–Lbc resulting in decreased PKA signaling facilitated by AKAP–Lbc. Expression of UCR1C in cardiomyocytes inhibits hypertrophy in response to chronic β-AR stimulation. This effect is partially due to inhibition of nuclear PKA activity, which decreases phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In conclusion, PDE4 activation by UCR1C attenuates cardiomyocyte hypertrophy by specifically inhibiting nuclear PKA activity.