2-Methoxyestradiol protects against pressure overload-induced left ventricular hypertrophy

Abstract

Numerous experimental studies have supported the evidence that 2-methoxyestradiol (2 ME) is a biologically active metabolite that mediates multiple effects on the cardiovascular system, largely independent of the estrogen receptor. 2 ME is a major cytochrome P450 1B1 (CYP1B1) metabolite and has been reported to have vasoprotective and anti-inflammatory actions. However, whether 2 ME would prevent cardiac hypertrophy induced by abdominal aortic constriction (AAC) has not been investigated yet. Therefore, the overall objectives of the present study were to elucidate the potential antihypertrophic effect of 2 ME and explore the mechanism(s) involved. Our results showed that 2 ME significantly inhibited AAC-induced left ventricular hypertrophy using echocardiography. The antihypertrophic effect of 2 ME was associated with a significant inhibition of CYP1B1 and mid-chain hydroxyeicosatetraenoic acids. Based on proteomics data, the protective effect of 2 ME is linked to the induction of antioxidant and anti-inflammatory proteins in addition to the modulation of proteins involved in myocardial energy metabolism. In vitro, 2 ME has shown a direct antihypertrophic effect through mitogen-activated protein kinases- and nuclear factor-κB-dependent mechanisms. The present work shows a strong evidence that 2 ME protects against left ventricular hypertrophy. Our data suggest the potential of repurposing 2 ME as a selective CYP1B1 inhibitor for the treatment of heart failure.

DPP4 Inhibition, NPY1-36, PYY1-36, SDF-1α, and a Hypertensive Genetic Background Conspire to Augment Cell Proliferation and Collagen Production: Effects That Are Abolished by Low Concentrations of 2-Methoxyestradiol

“…In this regard, 2HE reverses the metabolic syndrome (Tofovic et al, 2001); in mice on a high-fat diet, genetic deficiency, or inhibition of COMT (key enzyme for 2HE to 2ME conversion) leads to insulin resistance and 2ME treatment improves metabolic derangements (Kanasaki et al, 2017); and 2ME improves glucose tolerance in db/db mice (Yorifuji et al, 2011). Furthermore, in vivo, 2ME and/or 2HE attenuate cardiac, renal, lung, and systemic fibrosis induced by profibrotic toxins (puromycin, bleomycin), NO deficiency or by angiotensin II (Tofovic et al, 2009;Zhu et al, 2015a;Maayah et al, 2018;Salah et al, 2019). Finally, 2ME reduces blood pressure in rats with genetically, metabolic syndrome-, NO deficiency-, DOCA-, or Ang II-induced hypertension (Bonacasa et al, 2008;Yuan et al, 2013;Maayah et al, 2018;Salah et al, 2019).…”

“…Furthermore, in vivo, 2ME and/or 2HE attenuate cardiac, renal, lung, and systemic fibrosis induced by profibrotic toxins (puromycin, bleomycin), NO deficiency or by angiotensin II (Tofovic et al, 2009;Zhu et al, 2015a;Maayah et al, 2018;Salah et al, 2019). Finally, 2ME reduces blood pressure in rats with genetically, metabolic syndrome-, NO deficiency-, DOCA-, or Ang II-induced hypertension (Bonacasa et al, 2008;Yuan et al, 2013;Maayah et al, 2018;Salah et al, 2019). Therefore, the combination of 2ME and DPP4Is may be a highly effective strategy to manage type 2 diabetes and prevent its sequelae.…”

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

“…In contrast, in vitro 2ME exerts feedback inhibition on CYP1B1 activity [132] and inhibits aryl hydrocarbon receptor-mediated induction of CYP1B1 and downstream production of reactive metabolites. In vivo 2ME significantly inhibits CYP1B1 expression, reduces mid-chain hydroxyeicosatetraenoic acid (HETE) production, and attenuates pressure overload-induced cardiac remodeling [133].…”

2-Methoxyestradiol in Pulmonary Arterial Hypertension: A New Disease Modifier

“…Moreover, 2ME inhibits aryl hydrocarbon receptor-mediated induction of CYP1B1 and reduces CYP1B1 production of reactive metabolites. In vivo, 2ME significantly inhibits CYP1B1 expression and attenuates pressure overload-induced cardiac remodeling [78,79]. In vivo CYP1B1 inhibition by 2ME reduces biosynthesis of mid-chain hydroxyeicosatetraenoic acids (HETEs) [79], suggesting a significant role for CYP1B1 in arachidonic acid metabolism.…”

“…In vivo, 2ME significantly inhibits CYP1B1 expression and attenuates pressure overload-induced cardiac remodeling [78,79]. In vivo CYP1B1 inhibition by 2ME reduces biosynthesis of mid-chain hydroxyeicosatetraenoic acids (HETEs) [79], suggesting a significant role for CYP1B1 in arachidonic acid metabolism. Indeed, due to its lipoxygenase-like activity, CYP1B1 facilitates arachidonic acid metabolism into HETEs and epoxyeicosatrienoic acids (EETs) [80].…”