ALPK2 identified as promising new therapeutic target for treatment of heart failure

Tatsuya Yoshida, Mikito Takefuji, and Toyoaki Murohara in the Department of Cardiology, Nagoya University Graduate School of Medicine, identified an enzyme, alpha-kinase 2 (ALPK2) that is specifically expressed in the heart. They found that the enzyme may prevent a stiff heart through activating the gene TPM1 in heart muscle fibers. ALPK2 is a promising new therapeutic target for the treatment of heart failure, especially heart failure with preserved ejection function (HFpEF).

The number of heart failure patients is increasing worldwide. In particular, HFpEF is a growing global concern as it is incurable, potentially fatal, and there are limited drug therapy options. HFpEF patients are characterized by a heart that fails to relax properly during the filling phase, leading to insufficient blood flow to meet the body's needs.

The process of protein phosphorylation is central to regulating various functions in the body, including how well the heart pumps blood out. The process is controlled by enzymes called protein kinases, which add a phosphate group to specific amino acids on target proteins. This modification changes the protein's structure causing changes in its activity and interactions with other molecules. Disruptions in the enzyme's activity play a key role in hearts becoming stiff.

The group investigated the gene expression of 518 protein kinase enzymes, revealing ALPK2 as a heart-specific kinase of interest. To understand its role, they compared mice without the gene that creates the enzyme with those that had exceptionally high levels of the gene, leading to an abundance of ALPK2.

The mice with low levels showed increased weaknesses in the aging-related ability of the heart to relax and fill with blood. On the other hand, the mice with overexpression of ALPK2 had increased phosphorylation of the amino acid tropomyosin 1 (TPM1), a major regulator of heart contraction. As HFpEF patients have decreased TPM1, increased phosphorylation of TPM1 would likely have a protective effect against the disease.

ALPK2-overexpression suppressed progression of diastolic dysfunction. In addition, it improved lung weight, which is often used as an index of heart failure. HFpEF is a growing global concern due to limited drug therapy options. Currently, there are only two drugs for HFpEF: SGLT2 inhibitor and ARNI. The ALPK2/TPM1 regulatory axis may provide a unique therapeutic target for HFpEF, allowing the development of new treatment options that target ALPK2 in the future."

Tatsuya Yoshida, Department of Cardiology, Nagoya University Graduate School of Medicine