β-Arrestin mediates the Frank–Starling mechanism of cardiac contractility

Abstract

The Frank-Starling law of the heart is a physiological phenomenon that describes an intrinsic property of heart muscle in which increased cardiac filling leads to enhanced cardiac contractility. Identified more than a century ago, the Frank-Starling relationship is currently known to involve length-dependent enhancement of cardiac myofilament Ca 2+ sensitivity. However, the upstream molecular events that link cellular stretch to the length-dependent myofilament Ca 2+ sensitivity are poorly understood. Because the angiotensin II type 1 receptor (AT1R) and the multifunctional transducer protein β-arrestin have been shown to mediate mechanosensitive cellular signaling, we tested the hypothesis that these two proteins are involved in the Frank-Starling mechanism of the heart. Using invasive hemodynamics, we found that mice lacking β-arrestin 1, β-arrestin 2, or AT1R were unable to generate a FrankStarling force in response to changes in cardiac volume. Although wildtype mice pretreated with the conventional AT1R blocker losartan were unable to enhance cardiac contractility with volume loading, treatment with a β-arrestin-biased AT1R ligand to selectively activate β-arrestin signaling preserved the Frank-Starling relationship. Importantly, in skinned muscle fiber preparations, we found markedly impaired length-dependent myofilament Ca 2+ sensitivity in β-arrestin 1, β-arrestin 2, and AT1R knockout mice. Our data reveal β-arrestin 1, β-arrestin 2, and AT1R as key regulatory molecules in the Frank-Starling mechanism, which potentially can be targeted therapeutically with β-arrestin-biased AT1R ligands.cardiac function | hemodynamics | mechanotransduction | angiotensin II type I receptor | β-arrestin

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…The family of RAS has expanded to include peptides consisting of angiotensin-1-7 [ANG (1-7)], angiotensin-2-8 (ANG III), angiotensin-3-8 (ANG IV), and angiotensin-1-12 [ANG (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)]. ANG (1)(2)(3)(4)(5)(6)(7) is formed by the catalytic action of ACE2 on ANG II and is thought to balance the RAS system by promoting an antagonistic effect on the responses elicited by ANG II-AT 1 R such as vasodilation (278,280). ANG III is produced from ANG II by enzymatic cleavage by an aminopeptidase which fuels similar physiological responses as ANG II (1228).…”

“…ANG IV is cleaved from ANG III by another aminopeptidase and contributes to blood flow regulation, learning and memory, and neuronal development (363). ANG (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) has been reported to serve as an upstream renin-independent precursor peptide for ANG I and ANG II (15,734). ANG (1-9) is generated from ANG I by several carboxypeptidase-type enzymes, including carboxypeptidase A, cathepsin A, and ACE2 (767).…”

“…ANG (1-7) has been reported to elicit its effects through the GPCR Mas receptor whereby it mediates antagonistic effects of ANG II, including vasodilation and antihypertensive and antifibrosis effects (800). Similar to Mas activation by ANG (1)(2)(3)(4)(5)(6)(7), alamandine also promotes antihypertensive effects through the Mas-related GPCR member D, MrgD, to produce nitric oxide (NO) (542). Interestingly, MrgD appears to be a second receptor for ANG (1)(2)(3)(4)(5)(6)(7).…”

“…Production of angiotensin peptides is first initiated by the synthesis and processing of preprorenin in juxtaglomerular cells neighboring the renal glomerulus with subsequent proteolytic cleavage of the signal peptide, intracellular sorting of prorenin to dense-core secretory vesicles, and cleavage of the prosegment, producing catalytically active renin that is secreted in the systemic circulation. Classically, renin cleaves liver-derived angiotensinogen (AGT) into angiotensin I (ANG I), a decapeptide [ANG (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)] which is then further processed by angiotensin-converting enzyme (ACE) into the octapeptide ANG II [Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, ANG (1-8)] (462).…”

Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signaling

“…All mouse physiology experiments were carried out with the help of expertise and resources available within the Duke Cardiovascular Research Center Core Facility and according to published protocols (5,68,69). Mice that died after receiving anesthesia or became hypotensive during the course of the procedure, suggesting a surgical complication, were excluded.…”