Novel drug targets in clinical development for heart failure

George, Melvin; Rajaram, Muthukumar; Shanmugam, Elangovan; Vijayakumar, T.

doi:10.1007/s00228-014-1671-4

Cited by 19 publications

(19 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The development of CVD results from various impairments, including cardiomyocyte apoptosis, cardiac remodeling and hypertrophy in cardiac function (George et al, 2014;Fujita and Ishikawa, 2011). It was also suggested that cardiac oxidative stress, inflammation and fibrosis played a vital role in the development of CVD (Butts et al, 2015;Weldy et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The involvement of Nox4 in fine particulate matter exposure-induced cardiac injury in mice

Wu¹,

Zhang²

2018

J. Toxicol. Sci.

View full text Add to dashboard Cite

-Epidemiological studies have confirmed that ambient fine particulate matter (PM 2.5 ) exposure is associated with cardiovascular disease (CVD). However, the underlying mechanisms in PM 2.5 exposure-induced heart injury are largely unknown. It has been acknowledged that NADPH oxidase (Nox) 4 plays a critical role in CVD development. To investigate the acute effects of PM 2.5 on the mouse heart and the role of Nox4 in PM 2.5 exposure-induced cardiac injury, C57BL/6J mice were instilled with saline or 1.5, 3.0, 6.0 mg/kg BW PM 2.5 suspension for two weeks (five days per week). The levels of malondialdehyde (MDA), super oxide dismutase (SOD), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β in heart supernatants were determined using related kits. The expression of Nox4, p67 phox , p47 phox and p22 phox in heart tissue was evaluated by immunofluorescence staining or Western blotting, respectively. Protein levels of p53, Bax, Bcl-2 and Caspase-3 in the heart were examined using immunohistochemical staining and Western blotting. TUNEL assay was used to measure myocardial apoptosis. PM 2.5 exposure leads to obvious cardiac injury. PM 2.5 exposure increases MDA level and iNOS activity, and decreases activity of SOD in heart supernatants of mice. High levels of TNF-α and IL-1β in heart supernatants of mice with PM 2.5 instillation were determined. Nox4 and Noxassociated subunits such as p67 phox , p47 phox and p22 phox expression levels were increased in heart tissue of mice after PM 2.5 exposure. Additionally, PM 2.5 exposure causes myocardial apoptosis in the mouse heart. This study suggested that Nox4 is involved in PM 2.5 exposure-induced cardiac injury in mice.

show abstract

Section: Discussionmentioning

confidence: 99%

The involvement of Nox4 in fine particulate matter exposure-induced cardiac injury in mice

Wu¹,

Zhang²

2018

J. Toxicol. Sci.

View full text Add to dashboard Cite

show abstract

“…11 For this reason, SERCA2a has been a focal point for the development of an improved range of inotropic drugs. Pharmaceutical agents, such as the Na + /K + ATPase inhibitor istaroxime, that increase SERCA activity have been tested with some positive outcomes in experimental and clinical studies, 16 but such agents have other actions that may present problems. Another approach is to reverse the lowered SERCA expression level directly by gene therapy, and considerable effort has been made in this regard.…”

Section: Serca2amentioning

confidence: 99%

“…2). A number of currently used inotropic drugs act by increasing cAMP levels and thereby activating PKA, leading to increased PLN S 16 phosphorylation by pln in healthy heart under basal conditions, stimulated conditions, and in heart failure. a positive inotropic stimulus increases phosphorylation and dysinhibits serCa2a.…”

Section: Phospholamban Phosphorylationmentioning

confidence: 99%

“…8 PLN is phosphorylated at S 16 primarily by PKA downstream of β-adrenergic receptor activation. 27 PLN is dephosphorylated principally by protein phosphatase-1 (PP-1), and PKA further regulates the phosphorylation status of PLN by phosphorylating a PP-1 inhibitor known as inhibitor-1 (I-1) at T 35 , thereby increasing its inhibitory function (Fig.…”

Section: Phospholamban Phosphorylationmentioning

confidence: 99%

“…PLN is an inhibitor of SERCA2a in the dephosphorylated state, and this inhibition is relieved by phosphorylation. 8 PLN is phosphorylated, most importantly, by protein kinase A (PKA) on S 16 following activation of β-adrenergic receptors, and its phosphorylation results in heightened SERCA function, accelerated relaxation, and increased SR Ca 2+ content.…”

Section: Sarcoplasmic Reticulum Ca 2+ As a Target For Inotropic Therapymentioning

confidence: 99%

See 2 more Smart Citations

Novel Therapeutic Targets in Heart Failure: The Phospholipase Cβ1b–Shank3 Interface

Woodcock

Grubb

2015

Clinical Medicine Insights: Therapeutics

View full text Add to dashboard Cite

Inotropic agents are often used to improve the contractile performance of the failing myocardium, but this is often at a cost of increased myocardial ischemia and arrhythmia. Myocyte contractility depends on the release of Ca 2+ from the sarcoplasmic reticulum, and this Ca 2+ is subject to regulation by the phosphorylation status of phospholamban (PLN). Many currently used inotropic agents function by increasing the phosphorylation of PLN, but these also heighten the risk of ischemia. Another approach is to reduce the dephosphorylation of PLN, which can be achieved by inhibiting pathways upstream or downstream of the protein kinase Cα. Phospholipase Cβ1b is responsible for activating protein kinase Cα, and its activity is substantially heightened in failing myocardium. We propose phospholipase Cβ1b, a cardiac-specific enzyme, as a promising target for the development of a new class of inotropic agents. By reversing changes that accompany the transition to heart failure, it may be possible to provide well-tolerated improvement in pump performance.keywoRdS: cardiac contractility, inotropic agent, splice variant, protein scaffold CITaTIoN: Woodcock and grubb. novel therapeutic targets in heart Failure: the phospholipase Cβ1b-shank3 interface.

show abstract

Developing Drugs for Heart Failure With Reduced Ejection Fraction: What Have We Learned From Clinical Trials?

Hinder

Yi²,

Langenickel

2018

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

There remains a large unmet need for new therapies in the treatment of heart failure with reduced ejection fraction (HFrEF). In the early drug development phase, the therapeutic potential of a drug is not yet fully understood and trial endpoints other than mortality are needed to guide drug development decisions. While a true surrogate marker for mortality in heart failure (HF) remains elusive, the successes and failures of previous trials can reveal markers that support clinical Go/NoGo decisions.

show abstract

Novel drug targets in clinical development for heart failure

Abstract: Clinical trials in heart failure must be designed to minimize the risk of "drug failures." Nevertheless, it is hoped that in the days to come, drugs with superior efficacy and safety will eventually be produced from the surge of molecules that are in the pipeline.

Cited by 19 publications

References 62 publications

The involvement of Nox4 in fine particulate matter exposure-induced cardiac injury in mice

The involvement of Nox4 in fine particulate matter exposure-induced cardiac injury in mice

Novel Therapeutic Targets in Heart Failure: The Phospholipase Cβ1b–Shank3 Interface

Developing Drugs for Heart Failure With Reduced Ejection Fraction: What Have We Learned From Clinical Trials?

Contact Info

Product

Resources

About