ALPK2: A Heart-Specific Enzyme Offers New Hope for Heart Failure

An enzyme called alpha-kinase 2 (ALPK2) that is only found in the heart has been discovered by Tatsuya Yoshida, Mikito Takefuji, and Toyoaki Murohara from the Department of Cardiology at Nagoya University Graduate School of Medicine. They discovered that the enzyme may prevent a stiff heart by activating the TPM1 gene in cardiac muscle fibers. ALPK2 is a promising novel therapeutic target for heart failure, particularly heart failure with preserved ejection function (HFpEF) (1^✔ ✔Trusted Source
ALPK2 prevents cardiac diastolic dysfunction in heart failure with preserved ejection fraction

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What is Heart Failure with Preserved Ejection Function

The number of heart failure patients is growing worldwide. In particular, HFpEF is a major global issue since it is incurable, possibly deadly, and has few medication treatment choices. HFpEF patients are defined by a heart that fails to relax effectively during the filling phase, resulting in inadequate blood flow to fulfill the body's requirment.

Protein phosphorylation is essential for controlling many bodily functions, including how well the heart pumps blood out. Enzymes known as protein kinases manage the process by adding phosphate groups to certain amino acids on target proteins. This mutation alters the protein's structure, influencing its activity and interactions with other molecules. Disruptions in enzyme activity are a major cause of stiff hearts.

ALPK2: A Potential Game-Changer in Heart Failure Treatment

The researchers examined the gene expression of 518 protein kinase enzymes and discovered ALPK2 as a heart-specific kinase of relevance. To further understand its significance, researchers compared mice lacking the gene that produces the enzyme to those with extremely high levels of the gene, resulting in an abundance of ALPK2.

Mice with low levels exhibited significant impairments in the heart's aging-related ability to relax and fill with blood. Mice overexpressing ALPK2 displayed elevated phosphorylation of tropomyosin 1 (TPM1), a key regulator of cardiac contraction. Because HFpEF patients have lower levels of TPM1, enhanced TPM1 phosphorylation is expected to protect them against illness.

"ALPK2-overexpression inhibited the progression of diastolic dysfunction. Furthermore, it improved lung weight, which is frequently used as an indicator of heart failure," Yoshida concluded. "HFpEF is a developing global concern due to a lack of pharmacological therapeutic choices. Currently, there are only two treatments for HFpEF: SGLT2 inhibitors and ARNI. The ALPK2/TPM1 regulatory axis may present a unique therapeutic target for HFpEF, enabling the development of new ALPK2-targeted treatment approaches in the future."

Reference:

1. ALPK2 prevents cardiac diastolic dysfunction in heart failure with preserved ejection fraction - (https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202402103R)

Source-Medindia