Estrogen Receptor-α Non-Nuclear Signaling Confers Cardioprotection and Is Essential to cGMP-PDE5 Inhibition Efficacy

Fukuma, Nobuaki; Takimoto, Eiki; Ueda, Kazutaka; Liu, Pang‐Yen; Tajima, Miyu; Otsu, Yu; Kariya, Taro; Harada, Mutsuo; Toko, Haruhiro; Koga, Kaori; Blanton, Robert M.; Karas, Richard H.; Komuro, Issei

doi:10.1016/j.jacbts.2019.12.009

Cited by 29 publications

(19 citation statements)

References 56 publications

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“…Prior studies have shown PDE9 counters cardiac hypertrophy and depresses pro-fibrotic signaling cascades in non-obese males subjected to pressure-load stress, and this efficacy is independent of NO-signaling (24) . Whereas PDE5A-I does not augment myocardial cGMP in OVX females (23, 32) , here we show PDE9-I does (Figure S4a), and this suggested it might also counter cardiac stress in our model. PDE9-I improved ejection fraction over placebo in OVX mice (Figure 2a, p=0.001 for drug/group interaction) and attenuated a significant rise in LV mass with placebo (p=0.005 for interaction).…”

Section: Resultsmentioning

confidence: 51%

PDE9 Inhibition Activates PPARα to Stimulate Mitochondrial Fat Metabolism and Reduce Cardiometabolic Syndrome

Mishra

Hahn

Sadagopan

et al. 2021

Preprint

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Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show inhibiting cyclic-GMP selective phosphodiesterase-9A (PDE9-I) suppresses established diet-induced obesity and CMS in ovariectomized female and male mice. PDE9-I reduces abdominal, hepatic, and myocardial fat accumulation, stimulates mitochondrial activity in brown and white fat, and improves CMS, without altering activity or food intake. PDE9 localizes to mitochondria, and its inhibition stimulates lipolysis and mitochondrial respiration coupled to PPARa dependent gene regulation. PPARa upregulation is required for PDE9-I metabolic efficacy and is absent in non-ovariectomized females that also display no metabolic benefits from PDE9-I. The latter is compatible with estrogen receptor-a altering PPARa chromatin binding identified by ChIPSeq. In humans with heart failure and preserved ejection fraction, myocardial expression of PPARA and its regulated genes is reduced versus control. These findings support testing PDE9-I to treat obesity/CMS in men and postmenopausal women.

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Section: Resultsmentioning

confidence: 51%

PDE9 Inhibition Activates PPARα to Stimulate Mitochondrial Fat Metabolism and Reduce Cardiometabolic Syndrome

Mishra

Hahn

Sadagopan

et al. 2021

Preprint

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“…Except for the comorbidities increasing the risk of heart failure, basic research 32 supports the idea that estrogen deficiency is a main contributor in the development of heart failure in the post-menopausal state. Activation of the renin-angiotensin-aldosterone system (RAAS) occurs in response to low estrogen levels after menopause, coincident with a decline in NO usage and increased collagen synthesis.…”

Section: Discussionmentioning

confidence: 95%

Differences in perioperative cardiovascular outcomes in elderly male and female patients undergoing intra-abdominal surgery: a retrospective cohort study

Chu

Han

et al. 2021

J Int Med Res

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Objective Perioperative cardiovascular events constitute the majority of complications in noncardiac surgery. Older and female patients have been less investigated. We aimed to evaluate differences in perioperative cardiovascular outcomes by age and sex. Methods We enrolled 1079 patients (57.5 ± 17.0 years, 42.6% women) undergoing intra-abdominal surgery from July 2007 to June 2008 and compared occurrence of perioperative cardiac events by age (≥65 vs. <65 years) and sex. Multivariable logistic regression was used to investigate associations between age, sex, and outcomes. Results Age ≥65 years was associated with perioperative myocardial infarction (MI) (odds ratio [OR] 2.9, 95% confidence interval [CI]: 1.3–6.6) and total cardiovascular events (OR 2.4, 95% CI: 1.3–4.2). Age ≥65 years was associated with higher perioperative MI risks in men (OR 4.7, 95% CI: 1.3–17.6) than in women (OR 3.1, 95% CI: 1.2–8.3). Advanced age was associated with heart failure in women (OR 13.9, 95% CI: 1.7–110.5). Female sex was a risk factor for heart failure in elderly patients (OR 4.2, 95% CI: 1.1–15.7). Conclusions Advanced age appeared to be associated with increased perioperative cardiac risk but differed by sex. Tailored strategies should be considered with respect to the patient’s sex.

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“…A higher proportion of women among HFpEF patients might result from their higher life expectancy [72]. However, estrogen deficiency has been postulated as one of the contributors underlying HFpEF development in post-menopausal women [74][75][76]. Among HF-pEF patients, women have smaller LV dimensions with poorer diastolic reserve and higher LV filling pressures at rest and exercise [77].…”

Section: Practical Considerations On Clinical Profilesmentioning

confidence: 99%

On the search for the right definition of heart failure with preserved ejection fraction

et al. 2020

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The definition of heart failure with preserved ejection fraction (HFpEF) has evolved from a clinically based "diagnosis of exclusion" to definitions focused on objective evidence of diastolic dysfunction and/ /or elevated left ventricular filling pressures. Despite advances in our understanding of HFpEF pathophysiology and the development of more sophisticated imaging modalities, the diagnosis of HFpEF remains challenging, especially in the chronic setting, given that symptoms are provoked by exertion and diagnostic evaluation is largely conducted at rest. Invasive hemodynamic study, and in particularinvasive exercise testing, is considered the reference method for HFpEF diagnosis. However, its use is limited as opposed to the high number of patients with suspected HFpEF. Thus, diagnostic criteria for HFpEF should be principally based on non-invasive measurements. As no single non-invasive variable can adequately corroborate or refute the diagnosis, different combinations of clinical, echocardiographic, and/or biochemical parameters have been introduced. Recent years have brought an abundance of HF-pEF definitions. Here, we present and compare four of them: 1) the 2016 European Society of Cardiology criteria for HFpEF; 2) the 2016 echocardiographic algorithm for diagnosing diastolic dysfunction; 3) the 2018 evidence-based H 2 FPEF score; and 4) the most recent, 2019 Heart Failure Association HFA-PEFF algorithm. These definitions vary in their approach to diagnosis, as well as sensitivity and specificity. Further studies to validate and compare the diagnostic accuracy of HFpEF definitions are warranted. Nevertheless, it seems that the best HFpEF definition would originate from a randomized clinical trial showing a favorable effect of an intervention on prognosis in HFpEF.

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Estrogen Receptor-α Non-Nuclear Signaling Confers Cardioprotection and Is Essential to cGMP-PDE5 Inhibition Efficacy

Cited by 29 publications

References 56 publications

PDE9 Inhibition Activates PPARα to Stimulate Mitochondrial Fat Metabolism and Reduce Cardiometabolic Syndrome

PDE9 Inhibition Activates PPARα to Stimulate Mitochondrial Fat Metabolism and Reduce Cardiometabolic Syndrome

Differences in perioperative cardiovascular outcomes in elderly male and female patients undergoing intra-abdominal surgery: a retrospective cohort study

On the search for the right definition of heart failure with preserved ejection fraction

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