Orai1 protein opens new opportunities in the fight against heart attack

• A research group belonging to the Biomedicine Institute of Seville (IBiS) has described a mechanism activated after a myocardial infarction, involving the proteins Orai1, AC8, and CREB.

• These proteins are involved in the increase of calcium in the heart, which damages cardiac function and can lead to heart failure, with fatal consequences.

• Inhibiting Orai1 could be a new therapeutic strategy to prevent the progression of the disease after a heart attack, helping to reduce further damage.

Seville, March 21, 2024

Myocardial infarction is one of the leading causes of death worldwide. Nearly half of the patients with heart failure die within 5 years following the diagnosis, according to the WHO. In search of new approaches to reduce these figures, a multidisciplinary team, led by the Cardiovascular Pathophysiology Group of the Biomedicine Institute of Seville (IBiS), has recently described a possible therapeutic pathway. This involves an essential protein for the regulation of the calcium ion within cells, Orai1, which shows increased expression after a myocardial infarction.

This manifestation seems to be directly related to the possibility of suffering more severe, even lethal, consequences afterward. With the aim at a new therapeutic target, this research believes that new treatments could be prescribed with hopeful results for people affected by a myocardial infarction.

More heart failure after a heart attack

Following an episode of a heart attack, there is a high probability of developing heart failure.  "When a patient survives a myocardial infarction, a few months later they develop an adaptation mechanism called remodeling," explains Tarik Smani, head of the Cardiovascular Pathophysiology Group at IBiS. "This is characterized by hypertrophy and the appearance of fibrosis necessary to repair the infarcted area." In other words, the damaged tissue is repaired by another type of tissue, akin to scar tissue, points out Débora Falcón, a researcher in the team.

According to the research team, the problem arises when this, over time, starts to affect other parts of the heart: "When these mechanisms become chronic, the adaptation turns pathological, increasing hypertrophy and fibrosis throughout the heart, which significantly affects cardiac function." It is in all this complex relationship where the protein Orai1 takes center stage.

Image 1: Illustration showing genetic manipulation of Orai1 expression to improve heart function after a heart attack.

Created by E. Calderon-Sanchez, D. Falcon, T. Smani

Orai1, calcium, and heart problems

"Orai1 is a protein located in the cell membrane," indicates Tarik Smani, "forming an ionic channel that allows the entry of the Ca2+ ion [calcium ion]." The Ca2+ ion is essential for cardiac contraction, and it is also a second messenger responsible for activating multitudes of signaling pathways necessary for cellular function and survival. So, what does it have to do with heart failure? According to the expert, although the levels of this protein are low under normal circumstances, its expression skyrockets after a myocardial infarction. "This is where Orai1 plays a relevant role in the progression of the disease towards failure and, therefore, on the mortality and morbidity associated with the disease," confirms Smani.

"It is known that the expression of Orai1 is low in a physiological situation [state without notable alterations] but its expression increases significantly after the infarction, as we have demonstrated in our work." Researcher Falcón points out that it was not known how this change in expression occurred, something that this research sheds light on: "In this work, we demonstrate that Orai1 itself activates its overexpression after the infarction." According to the research team's in-depth analysis, other molecules and factors act as regulators in the mechanism, including adenylate cyclase 8 (AC8) and the CREB factor.

In search of new therapeutic targets

Understanding the problem entails envisioning a possible solution. This is precisely the case with the research in question. Indeed, Orai1, as described by the research team, presents itself as a good therapeutic target to reduce the consequences after a heart attack: "Our data lay a solid preclinical foundation on the efficacy of inhibiting the expression of Orai1 on improving cardiac function after an infarction," confirms Débora.

"Currently, the use of selective, tolerable Orai1 inhibitors in clinical trials in humans for pancreatitis and COVID-19 pneumonia has been approved with promising results (CM4620 and Auxora)." There are various ways to control the expression of Orai1: "one can target either AC8 or the regulatory protein of the expression of Orai1," continues Smani, "or Orai1 itself as a target protein." Thus, the number of potential treatments that could be used to combat the problems that occur after a myocardial infarction is growing.

"Our work provides preclinical evidence on the importance of this signaling pathway in the infarcted heart. It would be highly useful to test the mentioned drugs through a phase II clinical trial to evaluate the efficacy of the Orai1 inhibitor in preventing the progression of the disease towards heart failure," reaffirms the researcher, highlighting that their work shows evidence of the overexpression of Orai1 and AC8 in the ventricle in human samples from patients with heart failure of ischemic origin. "These indications," he concludes, "confirm that the pathway involving Orai1 and AC8 is active after the pathology."

Image 2: From left to right, E. Calderon-Sanchez, T. Smani, and D. Falcon, analyzing an image of marked heart cells

This work has been funded by the State Research Agency of the Ministry of Science, Innovation, and Universities, and the Ministry of Economic Transformation, Industry, Knowledge, of the Junta de Andalucía.

Reference: Inhibition of adenylyl cyclase 8 prevents the upregulation of Orai1 channel, which improves cardiac function after myocardial infarction

https://doi.org/10.1016/j.ymthe.2024.01.026 

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About IBiS

The Institute of Biomedicine of Seville (IBiS) is a multidisciplinary center focused on carrying out fundamental research on the causes and mechanisms of the most prevalent pathologies in the population and the development of new methods to diagnose and to treat diseases.

IBiS is made up of 42 consolidated groups and 42 affiliated groups led by researchers from the University of Seville, the Spanish National Research Council (CSIC) and the Virgen del Rocío and Virgen Macarena University Hospitals and Valme, organized around five thematic areas: Infectious Diseases and Immune System, Neurosciences, Onco-hematology and Genetics, Cardiovascular Pathology, Respiratory / Other Systemic Pathologies and Liver, Digestive and Inflammatory Diseases.

IBiS depends institutionally on the Department (Consejería) of Health and Consumption of the Junta de Andalucía; the Andalusian Health Service (SAS); the Department (Consejería) of University, Research and Innovation; the University of Seville and the Spanish National Research Council (CSIC). It is managed by the Public Foundation for the Management of Health Research in Seville (FISEVI).

More information:

Angeles Escudero

Unidad de comunicación| UCC+i

InstitutodeBiomedicinadeSevilla - IBiS

Campus Hospital Universitario Virgen del Rocío

Avda. Manuel Siurot s/n

41013 Sevilla

Tel 682730351

Email: comunicacion-ibis@us.es