# Myocardial infarction activates the 9p21.3 orthologous locus expression, but its absence does not alter cardiac pathophysiology in ischemia

## TL;DR

This study shows that a genetic region linked to heart disease is activated after a heart attack, but removing it in mice doesn't change heart damage or survival.

## Contribution

The study clarifies the role of the 9p21.3 locus in cardiac ischemia and challenges its involvement in post-MI pathophysiology.

## Key findings

- The 9p21.3 locus is activated in response to cardiac ischemia in mice.
- Deficiency in the 9p21.3 locus does not alter survival or cardiac pathology after MI.
- The locus may be more involved in CAD development than in MI outcomes.

## Abstract

Genetic variation in the 9p21.3 chromosomal region has one of the strongest associations known for coronary artery disease (CAD) that often leads to myocardial infarction (MI). This risk locus encodes a long noncoding RNA, ANRIL, which has been suggested to regulate the neighboring cyclin‐dependent kinase inhibitors 2A and B (Cdkn2A/B), the key regulators of cell proliferation. In this study, we aimed to clarify the role of the 9p21.3 risk locus in acute and chronic myocardial ischemia in mice. Mice carrying a deletion equivalent to the human CAD risk interval (Chr4Δ70kb/Δ70kb) and wild type mice were exposed to MI and followed until 5 days or 4 weeks. In the wild type mice, expression of a lncRNA, Ak148321, was increased after MI, and Cdkn2a was upregulated in chronic ischemia. Chr4Δ70kb/Δ70kb downregulated both Cdkn2a/b, but this did not affect the survival or cardiac pathology after MI. These results suggest that the 9p21.3 locus is activated in response to cardiac ischemia. However, deficiency in the risk locus does not play a role in the cardiac pathophysiology in mice, supporting the studies suggesting the risk locus being more involved in the development of CAD, rather than the subsequent MI.