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California: Globally, ischemic heart disease is the leading cause of death. myocardial infarction (MI), commonly referred to as a “heart attack”, is the first event in which a part of the heart dies as a result of inadequate coronary blood flow. Heart failureThis results in rebuilding of the heart wall and severe inflammation.
It is surprising, anti-inflammatory drugs are not able to prevent heart failure. Therefore they are not a standard component of post-MI care. However, the most effective cellular and molecular targets for inflammation may still be unknown.
In the August 28, 2024 issue of Nature, researchers University of California San Diego The laboratory of Dr. Kevin King, associate professor of bioengineering and medicine and a cardiologist at the Sulpizio Cardiovascular Center, reports the discovery of a new mechanism Inflammation of the heart This could expand therapeutic opportunities to prevent a heart attack from turning into a cardiac arrest.
Inflammation after MI has traditionally been attributed to professional immune cells such as neutrophils and macrophages that infiltrate the infarcted heart and respond to molecules in the debris of dying cells. The team was therefore surprised when they found that the proinflammatory “type I interferon (IFN) response” was activated not in the infarct, where the immune cells were concentrated, but rather in the border zone surrounding the infarct.
The borderzone has been a fascinating but under-studied region of the infarcted heart. It is where surviving heart muscle cells attempt to stabilize and even grow after being detached from their dying neighbouring cells. Unfortunately, the borderzone has proven to be a challenging region to study because it cannot be easily isolated from the rest of the heart. Researchers recently overcame this obstacle using methods based on single cell RNAseq and spatial transcriptomics, where cells in the borderzone are identified based on their patterns of gene expression.
to determine which cell type initiates border area swellingThe team created a library of conditional knockout mice, each of which was unable to initiate IFN signaling To their surprise, heart muscle cells called cardiomyocytes emerged as the key initiators of borderzone IFN signaling. They found that mechanically stressed cardiomyocytes in the borderzone often suffered from nuclear envelope rupture, allowing nuclear DNA to escape and be sensed by cytosolic DNA sensors, thereby activating IFN signaling. This resulted in a mechanical weakening of the heart wall and rendering it vulnerable to dilatation, thinning, and rupture, providing a mechanistic explanation for the team’s previously reported observation that mice lacking IFN responses exhibited improved survival after MI. “In the hospital, we care for patients with heart attacks and heart failure every day. New therapeutic targets for MI are incredibly important with the potential to prevent the development of heart failure,” said Dr. King, senior author of the study and on faculty in the Shu Chien Jean Le Department of Bioengineering and the Division of Cardiology at UC San Diego.
Many questions still remain, although recent findings suggest that limiting mechanical stresses in the boundary region, DNA sensingAnd inhibiting type I IFN signaling may represent new opportunities for patients to avoid developing heart failure after MI.
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