Serelaxin and the AT₂ Receptor Agonist CGP42112 Evoked a Similar, Nonadditive, Cardiac Antifibrotic Effect in High Salt-Fed Mice That Were Refractory to Candesartan Cilexetil

Abstract

Fibrosis is involved in the majority of cardiovascular diseases and is a key contributor to end-organ dysfunction. In the current study, the antifibrotic effects of recombinant human relaxin-2 (serelaxin; RLX) and/or the AT 2 R agonist CGP42112 (CGP) were compared with those of the established AT 1 R antagonist, candesartan cilexetil (CAND), in a high salt-induced cardiac fibrosis model. High salt (HS; 5%) for 8 weeks did not increase systolic blood pressure in male FVB/N mice, but CAND treatment alone significantly reduced systolic blood pressure from HS-induced levels. HS significantly increased cardiac interstitial fibrosis, which was reduced by either RLX and/or CGP, which were not additive under the current experimental conditions, while CAND failed to reduce HS-induced cardiac fibrosis. The antifibrotic effects induced by RLX and/or CGP were associated with reduced myofibroblast differentiation. Additionally, all treatments inhibited the HS-induced elevation in tissue inhibitor of matrix metalloproteinases-1, together with trends for increased MMP-13 expression, that collectively would favor collagen degradation. Furthermore, these antifibrotic effects were associated with reduced cardiac inflammation. Collectively, these results highlight that either RXFP1 or AT 2 R stimulation represents novel therapeutic strategies to target fibrotic conditions, particularly in HS states that may be refractory to AT 1 R blockade.

Preclinical rodent models of cardiac fibrosis

“…The level of collagen deposition induced by HS diets can vary between different mouse strains even without an elevation of blood pressure. We found that 5% HS diet for 8 weeks was able to increase cardiac fibrosis (by ~1.5‐fold using Picrosirius Red staining and hydroxyproline analysis) in FVB/N mice (Wang et al, 2020), whereas Le Corvoisier et al (2010) found a more than threefold increase in cardiac interstitial fibrosis using a similar protocol (4% HS diet for 8 weeks) in Swiss mice using the same methodology. Longer periods of 4% HS intake (e.g., 15 weeks) did not further increase interstitial fibrosis in the left ventricle (LV) of WKYs (Ferreira et al, 2010).…”

“…For example, 4% HS diet increased cardiac fibrosis in obese Zucker rats (Ali et al, 2015), Dahl salt‐sensitive (DSS) rats (Pushpakumar et al, 2013), as well as in the presence of Ang II (Gonzalez et al, 2015), and all these animals demostrated elevated blood pressure. However, the 4% HS‐induced cardiac fibrosis was not associated with increased blood pressure in Lewis rats (Pushpakumar et al, 2013), Swiss mice (Le Corvoisier et al, 2010) or FVB/N mice (Wang et al, 2020). Therefore, an appropriate salt concentration is essential for experimental design depending on whether blood pressure‐dependent or ‐independent remodelling is to be considered.…”

“…When using a higher salt concentration (8% NaCl), a slightly higher level of cardiac collagen deposition was observed in WKYs (approximately twofold increase) and SHRs or DSS rats (approximately threefold increase) compared with normal salt (NS) diet‐fed rats, which eventually led to diastolic dysfunction (Hayakawa et al, 2015; Kimura et al, 2019). Importantly, chronic HS diets not only induce cardiac remodelling but also induce renal damage and metabolic disorders, such as insulin resistance and dyslipidaemia (Wang et al, 2020; Yu et al, 1998).…”

Male bias in ACE2 basic science research: missed opportunity for discovery in the time of COVID-19

“…Excessive Ang-[1–8] activity at the angiotensin type 1 receptor (AT 1 R) leads to hypertension, inflammation, atherogenesis, and tissue fibrosis ( 1 , 2 ). The angiotensin type 2 receptor (AT 2 R) plays a counter-regulatory role in AT 1 R actions, especially in the females ( 3 , 4 ).…”

Emerging Leaders in Pharmacology and Translational Science Special Issue Editorial

“…This class of endogenously generated mediators (and four generations of newer synthetic analogues with progressively increasing potency) promote the resolution of inflammation via the GPCR formyl peptide receptor-2 (FPR2), facilitating the healing process and restoration of tissue homeostasis in a range of settings of inflammation. The study reported by Wang et al describes the protective actions observed in response to the novel antifibrotic agent, relaxin, as well as to an angiotensin AT2 receptor agonist, alone and in combination, in a high salt diet model of cardiac fibrosis. These actions were accompanied by the blunting of cardiac inflammation but were independent of the lowering of blood pressure.…”