Beta-Arrestins in the Treatment of Heart Failure Related to Hypertension: A Comprehensive Review

Figures

• 

  Figure 1. The functional distinction between β-arrestin1 and β-arrestin2 in cardiac myocytes. SR: sarcoplasmic reticulum; SUMO1: small ubiquitin-like modifier protein-1; EGFR: epidermal growth factor receptor; and AR: adrenergic receptor.

• 

  Figure 2. The renin–angiotensin–aldosterone system is a key regulator of blood pressure. Renin cleaves angiotensinogen into angiotensin I, which is further cleaved by ACE inhibitors to form angiotensin II. Here, two distinct pathways are possible. (1) Angiotensin II activates the AT1R and elicits vasoconstriction or aldosterone secretion, which eventually raises blood pressure. (2) Angiotensin II is cleaved by ACE2 or other carboxypeptidases to generate the heptapeptide Ang-(1–7), which is also responsible for β-arrestin1 and β-arrestin2 recruitment, giving both detrimental and salutary effects in terms of the cardiovascular system and VSM.

• 

  Figure 3. Effects of β-arrestin1 on the cellular cAMP level. (A) β-arrestin1 elevates the phosphorylation of ERK1/2, resulting in a decreased amount of cAMP. (B) β-arrestin 1 inhibits Gs/protein/cAMP-dependent pro-contractile signaling, which eventually reduces the cellular cAMP level in β1AR. (C) β-arrestin1 involves PDE4 recruitment, ultimately causing a decreased cAMP level.

• 

  Figure 4. β-arrestin2 affects the production of NO. Along with GRK2, β-arrestin2 inhibits phosphorylation of the Akt/eNOS pathway, which decreases the amount of NO production. Furthermore, β-arrestin2 impedes NF-κB signaling by stabilizing IκBα, resulting in a decrease in NOS II expression and eventually decreasing the rate of NO production. Altogether, the result is increased blood pressure.

• 

  Figure 5. The renalase pathway. Catecholamines stimulate renalase synthesis through increasing renalase secretion from prorenalase, increased enzymatic activity, and enhanced gene transcription. Activated renalase then degrades catecholamines into their metabolites. Renalase decreases hypertension by decreasing the heart rate and cardiac contractility. However, β-arrestin1 expression causes an excessive amount of catecholamine synthesis, which further inhibits the beneficial action of renalase.

• 

  Figure 6. Inhibiting ROCK activity causes vasodilation, leading to blood pressure reduction. ROCK inhibition is mediated by declined RhoA activity, specific AT1R inhibition, a decreased amount of ROS, and increased NO production. However, both β-arrestin1 and β-arrestin2 are associated with decreasing the amount of NO. Moreover, β-arrestin2 impedes the activity of sorafenib, a ROCK inhibitor.