New Therapeutic Target Discovered for Lethal Form of Heart Failure

Researchers discovered that ALPK2, a heart-specific enzyme, may protect against HFpEF by activating TPM1 in heart muscle fibers.

Researchers Tatsuya Yoshida, Mikito Takefuji, and Toyoaki Murohara from the Department of Cardiology at Nagoya University Graduate School of Medicine have identified alpha-kinase 2 (ALPK2), an enzyme specifically expressed in the heart. Their study suggests that ALPK2 plays a crucial role in preventing cardiac stiffness by activating the TPM1 gene in heart muscle fibers. This discovery positions ALPK2 as a promising therapeutic target for treating heart failure, particularly heart failure with preserved ejection fraction (HFpEF).

Heart failure is a growing global health concern, with HFpEF emerging as a particularly challenging condition due to its limited treatment options and high mortality risk. HFpEF occurs when the heart struggles to relax properly during the filling phase, leading to inadequate blood flow to meet the body’s demands. Given the urgent need for effective therapies, ALPK2 could represent a significant breakthrough in addressing this life-threatening condition.

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 are a set of organic compounds used to build proteins. There are about 500 naturally occurring known amino acids, though only 20 appear in the genetic code. Proteins consist of one or more chains of amino acids called polypeptides. The sequence of the amino acid chain causes the polypeptide to fold into a shape that is biologically active. The amino acid sequences of proteins are encoded in the genes. Nine proteinogenic amino acids are called “essential” for humans because they cannot be produced from other compounds by the human body and so must be taken in as food.

” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>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.

Investigating ALPK2’s Role in Heart Function

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 the progression of diastolic dysfunction. In addition, it improved lung weight, which is often used as an index of heart failure,” Yoshida summarized. “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.”

Reference: “ALPK2 prevents cardiac diastolic dysfunction in heart failure with preserved ejection fraction” by Tatsuya Yoshida, Satoya Yoshida, Kohei Inukai, Katsuhiro Kato, Yoshimitsu Yura, Tomoki Hattori, Kentaro Taki, Atsushi Enomoto, Koji Ohashi, Takahiro Okumura, Noriyuki Ouchi, Haruya Kawase, Nina Wettschureck, Stefan Offermanns, Toyoaki Murohara and Mikito Takefuji, 18 November 2024, The FASEB Journal.
DOI: 10.1096/fj.202402103R