Diverse Regulation of Cardiac Expression of Relaxin Receptor by α1- and β1-Adrenoceptors

Moore, Xiao‐Lei; Su, Yidan; Fan, Yi‐Ming; Zhang, Youyi; Woodcock, Elizabeth A.; Dart, Anthony M.; Du, Xiao‐Jun

doi:10.1007/s10557-014-6525-x

Cited by 17 publications

(12 citation statements)

References 39 publications

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“…Our findings indicate that the cytoprotection afforded by RLX is more potent when the hormone was added before the occurrence of hypoxia than at the onset of reoxygenation. This notion, taken together with the previous reports that cardiomyocytes produce RLX (10) and express specific RLX receptors (11, 12), strongly suggests that RLX could be an endogenous cardiac factor involved in the mechanisms of myocardial preconditioning. Further clues in support to this hypothesis come from the observations that plasma RLX is increased in patients with cardiac failure (56), suggesting that RLX may be released from the injured heart as an attempt to compensate for noxious conditions; and Notch‐1 signaling has been recognized as a major endogenous mechanism involved in heart pre‐ and postconditioning (28, 29).…”

Section: Discussionmentioning

confidence: 63%

“…Whether RLX may also behave as a direct protective factor for cardiomyocytes is a tantalizing but poorly explored matter. Indeed, this hypothesis is corroborated by the findings that ventricular cardiomyocytes express the specific RLX receptor RXFP1 (12) and that RLX protects cardiomyocytes against oxidative stress-induced apoptosis in vitro (27). A strictly related issue to investigate is related to the intracellular mechanisms by which RLX may exert cardioprotection.…”

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confidence: 83%

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Relaxin protects cardiac muscle cells from hypoxia/reoxygenation injury: involvement of the Notch‐1 pathway

et al. 2014

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In animal models, the cardiotropic hormone relaxin has been shown to protect the heart against ischemia and reperfusion-induced damage, acting by multiple mechanisms that primarily involve the coronary vessels. This in vitro study evaluates whether relaxin also has a direct protective action on cardiac muscle cells. H9c2 rat cardiomyoblasts and primary mouse cardiomyocytes were subjected to hypoxia and reoxygenation. In some experiments, relaxin was added preventatively before hypoxia; in others, at reoxygenation. To elucidate its mechanisms of action, we focused on Notch-1, which is involved in heart pre-and postconditioning to ischemia. Inactivated RLX was used as negative control. Relaxin (17 nmol/L, EC 50 4.7 nmol/L), added 24 h before hypoxia or at reoxygenation, protected against cardiomyocyte injury. In fact, relaxin significantly increased cell viability (assayed by trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), decreased apoptosis (assayed by TUNEL and bax/bcl-2 ratio), and reduced nitroxidative damage (assayed by nitrotyrosine expression and 8-hydroxy-deoxyguanosine levels). These effects were partly attributable to the ability of relaxin to upregulate Notch-1 signaling; indeed, blockade of Notch-1 activation with the specific inhibitor DAPT reduced relaxin-induced cardioprotection during hypoxia and reoxygenation. This study adds new mechanistic insights on the cardioprotective role of relaxin on ischemic and oxidative damage.-Boccalini, G., Sassoli, C., Formigli, L., Bani, D., Nistri, S. Relaxin protects cardiac muscle cells from hypoxia/reoxygenation injury: involvement of the Notch-1 pathway. FASEB J. 29, 239-249 (2015). www.fasebj.orgCARDIOVASCULAR DISEASE is the leading cause of death in modern society worldwide (1). In particular, cardiac dysfunction caused by nonlethal myocardial infarction remains one of the most challenging clinical problems. The pathogenic occurrences in the infarcted heart are dependent on ischemia/reperfusion (I/R). The mechanisms of I/R injury are complex and involve multiple events, basically nitroxidative stress (2, 3) and inflammation (4), that play a key role in the progression of cardiac damage and in the development of myocardial fibrosis and heart failure (5). Hence, there is a major interest in the identification of new therapeutic agents that can prevent or reduce I/R-induced myocardial injury. In this context, the hormone relaxin (RLX) emerges as a feasible candidate. Best known for its effects on reproduction (6), RLX has been validated as a bona fide cardiovascular hormone (7-9). Studies in rats have shown that immunoreactive RLX is produced by cultured atrial cardiomyocytes (10) and that RLX receptors are expressed by the atrial and ventricular myocardium (11) and ventricular cardiomyocytes (12). RLX is capable of enhancing cardiac blood perfusion by dilating the preexisting coronary vessels (13) and promoting neo-angiogenesis (14, 15). The increased blood supply to the heart induced by RLX, accompanied by its clear-cu...

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Section: Discussionmentioning

confidence: 63%

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confidence: 83%

Relaxin protects cardiac muscle cells from hypoxia/reoxygenation injury: involvement of the Notch‐1 pathway

et al. 2014

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“…However, it is becoming increasingly apparent that several class A GPCRs 61 including AT1R and AT2R 35 , and RXFP1 25,62 form heteromers or receptor complexes that are required to modulate function. RXFP1 is widely expressed in several organs 5 including the kidney and heart, is moderately decreased following injury in the rodent 63 and human 64 heart, and is down-regulated by 1-adrenoceptor stimulation but up-regulated by 1-adrenoceptor stimulation 65 . AT1Rs are also widely distributed throughout the heart and kidney in both healthy and diseased states, but are significantly increased in expression in rodents and humans undergoing injury or disease, particularly when the renin angiotensin system (RAS) is upregulated 66 .…”

Section: Discussionmentioning

confidence: 99%

AT1R-AT2R-RXFP1 Functional Crosstalk in Myofibroblasts: Impact on the Therapeutic Targeting of Renal and Cardiac Fibrosis

Chow

Kočan

Shen

et al. 2019

JASN

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Background Recombinant human H2 relaxin (serelaxin) has emerged as a potential agent to treat fibrosis, the pathological hallmark of chronic disease. As we now know that serelaxin requires the angiotensin II (Ang II) type 2 receptor (AT2R) to ameliorate renal fibrogenesis in vitro and in vivo, we sought to determine if its anti-fibrotic actions were affected by Ang II type 1 receptor (AT1R) modulation. Methods We examined the signal transduction mechanisms of serelaxin when applied to primary rat renal and human cardiac myofibroblasts in vitro, and in three models of renal-or cardiomyopathy-induced fibrosis in vivo. Results The anti-fibrotic signal transduction of serelaxin via its cognate receptor, relaxin family peptide receptor 1 (RXFP1), was abrogated by the AT1R blockers, irbesartan or candesartan in vitro and in vivo. Candesartan also ameliorated serelaxin's anti-fibrotic actions in the left ventricle of mice with cardiomyopathy, indicating that the inhibitory effects of candesartan were not confined to the kidney. In a transfected cell system, we demonstrated that serelaxin did not directly bind to AT1Rs but that constitutive AT1R-RXFP1 interactions could form. To potentially explain these findings, we also demonstrated that all three receptors were expressed by renal and cardiac (myo)fibroblasts and that antagonists acting at each receptor directly/allosterically blocked the anti-fibrotic effects of either serelaxin or the AT2R agonist, Compound 21. Conclusions These findings have significant implications for the concomitant use of RXFP1 or AT2R agonists with AT1R blockers and suggest that functional AT1R-AT2R-RXFP1 interactions on myofibroblasts may represent new targets for controlling fibrosis progression.

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“…Little is known, however, about the transcriptional regulation of RXFP1 expression. Many endocrine signals have been associated with RXFP1 expression (8,9). We and others have shown that transforming growth factor (TGF) ␤ stimulation can lead to decreased RXFP1 expression (7,10).…”

Section: The Hormone Relaxin Is Considered a Potential Therapy For Idmentioning

confidence: 99%

MicroRNA-144-3p targets relaxin/insulin-like family peptide receptor 1 (RXFP1) expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis

Bahudhanapati

Tan

Dutta

et al. 2019

Journal of Biological Chemistry

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Diverse Regulation of Cardiac Expression of Relaxin Receptor by α1- and β1-Adrenoceptors

Abstract: Expression of RXFP1 was up-regulated by α1-AR but suppressed by β-AR, mainly β1-AR subtype, in cardiomyocytes. Future studies are warranted to characterize the functional significance of such regulation, especially in the setting of heart failure.

Cited by 17 publications

References 39 publications

Relaxin protects cardiac muscle cells from hypoxia/reoxygenation injury: involvement of the Notch‐1 pathway

Relaxin protects cardiac muscle cells from hypoxia/reoxygenation injury: involvement of the Notch‐1 pathway

AT1R-AT2R-RXFP1 Functional Crosstalk in Myofibroblasts: Impact on the Therapeutic Targeting of Renal and Cardiac Fibrosis

MicroRNA-144-3p targets relaxin/insulin-like family peptide receptor 1 (RXFP1) expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis

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