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Research led by Dr Alzbeta Hulikova and Professor Pawel Swietach has, for the first time, described the potential regulation of nuclear acid-base chemistry in neonatal and adult cardiomyocytes, and explained its relevance in the context of heart physiology and pathology.

Map of nuclear and cytoplasmic pH recorded in neonatal cardiac cells incubated in various medium pH: 6.24, 6.49, 6.80. 6.98, 7.10 and 7.45. This is colour coded on a scale from 6.1 - 7.6 pH.
Map of nuclear and cytoplasmic pH recorded in neonatal cardiac cells incubated in various medium pH

Intracellular pH has to be tightly regulated in all cells of our body, including cardiac myocytes, as protons (H+) can have a significant impact on protein activity and cellular function. Changes in intracellular pH also often accompany cardiac development or heart pathology.

New research led by Dr Alzbeta Hulikova and Professor Pawel Swietach has shown that early postnatal heart muscle cells show a large diversity in extracellular pH. This can have a significant impact on shaping the cardiac gene expression shortly after birth.

Therefore, researchers have focused on the effect of extracellular pH on gene expression in the heart muscle. By growing cardiac myocytes from neonatal rats in media with different pH, the team were able to identify genes which are pH-sensitive. Most of these pH-sensitive genes are related to cardiac muscle contraction.

Researchers discovered that the expression of genes important for cardiac contraction is dependent on the transcriptional co-factor p300/CBP. They have shown that p300/CBP level of acetylation, namely activity dropped when cells were grown in acidic medium. This was confirmed by ChiP-sequencing, which proved that the acetylation level of histone3 Lys 27 (H3K27Ac) decreased in promoters of the most pH sensitive genes coding for Crip2 and slow skeletal troponin I (Tnni1).

As the regulation of gene expression takes place in the nucleus, Dr Hulikova and her team wanted to directly measure nuclear pH.  They were the first to map the relationship between nuclear and cytoplasmic pH. The team's measurements have shown that nuclear pH regulation is partially independent from the pH regulation in cytoplasm. Neonatal cardiac myocytes tend to have a slightly more alkaline nucleoplasm than cytoplasm. Whereas in healthy paced adult myocytes the nuclei were mildly acidic compared to the surrounding cytoplasm. Using different salt concentration and small molecule inhibitors we have shown that the SERCA and NHE1 transporters are likely to be involved in the maintenance of pH differences across nuclear envelope. These nuclear pH differences are important in heart pathology, and are significantly dysregulated in myocytes from cryo-infarcted adult rats or sheep with heart failure.

For the first time, researchers have described the possible regulation of nuclear acid-base chemistry in neonatal and adult cardiomyocytes. In doing so, they explain how it is relevant in the context of heart physiology and cardiac development, and in pathology, namely cardiac ischaemia and heart failure.

The full paper "Alkaline nucleoplasm facilitates contractile gene expression in the mammalian heart" is available to read in "Basic Research in Cardiology". 

Text credit to Dr Alzbeta Hulikova

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