According to the American Heart Association, heart failure causes chronic inflammation and affects about 6 million Americans with many in need for a heart transplant. The two most common causes are high blood pressure and coronary artery disease. Currently there is no treatment that can stop progression of heart failure. About half of patients die within the first five years of their diagnosis. There is a pressing need for novel treatments to address some specific underlying mechanisms of the disease. Researchers at The Ohio State University Wexner Medical Center and College of Medicine have developed a novel drug molecule that targets T-cells causing inflammation in heart failure patients, stopping further progression of the disease. During heart failure, T lymphocytes go from protecting the body from infection to causing heart failure to progress. In a research of heart failure mice, Ohio State University researchers found these “bad” T-cells have increased levels of estrogen receptor alpha (ER-a) that binds female hormones.
With the help of the Drug Development Institute, researchers identified and tested a new drug molecule that activates estrogen receptor beta (ER-β), which is known to have an opposite effect of estrogen receptor alpha. The cardioprotective role of ERβ has been highlighted in the recent years. Isolated female mouse hearts lacking ERβ are less protected against ischemia-riperfusion injury compared to wild-type female mice. Activation of ERβ via a specific ERβ agonist prior to the injury has been shown to improve cardiac recovery by decreasing apoptosis and preserving mitochondrial integrity in female mice in vivo. And altogether, the two types of estrogen receptors have each one a proper role: ERα has been shown to reduce infarct size, decrease ROS production, attenuate myocyte apoptosis, and inhibit the complement system. ERβ activation has been shown to attenuate apoptosis and decrease oxidative stress.
The novel drug stopped progression of heart failure and Ohio State University has patented the molecule called OSU-ERb-012. Proliferation assays of T lymphocytes in vitro showed that OSU-ERb-012 dose-dependently inhibited proliferation and proinflammatory cytokine expression in anti-CD3/CD28 stimulated splenic T cells isolated from both the sexes. For in vivo efficacy, 10- to 12-week-old male and ovariectomized female mice were randomized at 4 weeks post-infarction and treated orally with either inactive vehicle or the drug (60 mg/kg/day). Additionally, OSU-ERb-012 selectively inhibited cardiac, splenic and circulating CD4+ T cells in the sick mice without affecting other myeloid and lymphoid cells. It has to be highlighted that these effects belong to the immune system. Estrogen themselves through ER-alpha are cytoprotective in heart muscle fibers either in health that during chronic heart failure (CHF).
ER-alpha, indeed, activates also non-genomic signaling that involve the PI3K-Akt signaling cascade. This is notoriously anti-apoptotic and protects cells against the cellular death casued by the progression of the disease. However ER-alpha activity in immune cells might not be suitable during a pathology, in this case chronic heart failure. Estrogens prone immune cells toward the auto-reactivity like it happens in diseases like systemic lupus in rheumatoid arthritis. Females are particularly prone to these kind of autoimmune conditions, exactly due to their estrogen background. It is possible to see this anomalous immune component in CHF in a similar way seen in lupus or rheumatoid arthritis, where estrogen puts the genetic background under pressure for the development of the autoimmunity. Scientists are now planning to determine the effectiveness of the drug in other animal trials, identify the lowest therapeutic dose and eventually conduct clinical trials in human heart failure patients.
Shyam S. Bansal, assistant professor in the Department of Physiology and Cell Biology and investigator at the Dorothy M. Davis Heart and Lung Research Institute, commented righteously on the issue: “This is a major finding since we have not had a new drug developed for heart failure in the last several years. We know inflammation plays an important role in worsening symptoms of heart failure, but we have not been able to identify suitable treatments that can target ‘bad’ inflammation without affecting ‘good’ inflammation. With this drug, we can selectively target ‘bad’ T-cells and stop the disease from getting worse”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Rosenzweig R, et al. Circ Heart Fail 2022 Jun 22:121008997.
Hajializadeh Z et al. Heart Failure Rev. 2022; 27(2):725-738.
Xiang D et al. Oxid Med Cell Longev. 2021; 2021:5523516.
Aryan L, Younessi D et al. Int J Mol Sci. 2020; 21(12):4314.
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