Recombinant Human Relaxin-2: (How) Can a Pregnancy Hormone Save Lives in Acute Heart Failure?

Abstract

Acute heart failure (AHF) syndrome, characterized by pulmonary and/or venous congestion owing to increased cardiac filling pressures with or without diminished cardiac output, is still associated with high post-discharge mortality and hospitalization rates. Many novel and promising therapeutic approaches, among them endothelin-1, vasopressin and adenosine antagonists, calcium sensitization, and recombinant B-type natriuretic hormone, have failed in large studies. Likewise, the classic drugs, vasodilators, diuretics, and inotropes, have never been shown to lower mortality.The phase III trial RELAX-AHF tested recombinant human relaxin-2 (rhRlx) and found it to improve clinical symptoms moderately, to be neutral regarding the combination of death and hospitalization at day 60, to be safe, and to lower mortality at day 180. This review focuses on basic research and pre-clinical findings that may account for the benefit of rhRlx in AHF. The drug combines short-term hemodynamic advantages, such as moderate blood pressure decline and functional endothelin-1 antagonism, with a wealth of protective effects harboring long-term benefits, such as anti-inflammatory, anti-fibrotic, and anti-oxidative actions. These pleiotropic effects are exerted through a complex and intricate signaling cascade involving the relaxin-family peptide receptor-1, the glucocorticoid receptor, nitric oxide, and a cell type-dependent variety of kinases and transcription factors.

Relaxin-2 in Cardiometabolic Diseases: Mechanisms of Action and Future Perspectives

“…In contrast, other mammals have only the RLN-1 and RLN-3 genes. Importantly, the RLN-2 gene in humans and the RLN-1 gene from other mammals are equivalent and encode the relaxin peptides that circulate in blood during pregnancy, being RLN-2 in humans and great apes and RLN-1 in other non-primate species commonly referred to as relaxin (Wilkinson et al, 2005 ; Bathgate et al, 2013 ; in this review we will refer to RLX-2 and RLX-1 as relaxin), while the peptide encoded by the RLN-3 gene is a neuropeptide in all species (Figure 1 ; Dschietzig, 2014 ).…”

Does serelaxin treatment alter passive mechanical wall properties in small resistance arteries?

“…Serelaxin treatment improves renal function by increasing renal plasma flow, glomerular filtration rate and plasma volume and decreasing plasma osmolality . These hemodynamic changes and improvements in renal function are largely attributed to the endothelium‐dependent reduction in myogenic reactivity/tone in the small renal arteries (segmental and interlobar) . Serelaxin increases MMP‐2 and MMP‐9 activity, which converts big endothelin to endothelin 1‐32 .…”

“…19 These hemodynamic changes and improvements in renal function are largely attributed to the endothelium-dependent reduction in myogenic reactivity/tone in the small renal arteries (segmental and interlobar). [20][21][22][23] Serelaxin increases MMP-2 and MMP-9 activity, which converts big endothelin to endothelin . This activates endothelial endothelin B receptors, leading to increased endothelial nitric oxide synthase activity and production of nitric oxide, thereby reducing both vascular tone and myogenic reactivity.…”

Active vitamin D3, 1,25-(OH)2D3, protects against macrovasculopathy in a rat model of type 2 diabetes mellitus

“…As an inflammatory factor, TNF-α can act directly on the vascular endothelium to promote thrombosis and the formation of AS plaques. Endothelin (ET) is a potent vasoconstrictor peptide, which promotes the proliferation of smooth muscle cells (Dschietzig, 2014). The synthesis and release of ET is enhanced in response to endothelial injury (Liu et al, 2014;Zhao et al, 2015), and the production of ET by endothelial cells can promote the development of AS (Broder et al, 2013).…”