Researchers Identify Potential Therapeutic Targets for PH Associated with Heart Failure

A new study identified two potential therapeutic targets for pulmonary hypertension (PH) associated with heart failure. The two related enzymes, named ROCK1 and ROCK2, were seen to exert opposing effects on heart muscle cells, either preventing or promoting PH, in mouse models of heart failure.

Scientists also found a drug that can reduce the activity of two downstream targets of these enzymes, and relieve heart failure and PH signs in mice.

The study, “Different Roles of Myocardial ROCK1 and ROCK2 in Cardiac Dysfunction and Postcapillary Pulmonary Hypertension in Mice” was published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

By building on research suggesting important roles for ROCK1 and ROCK2 in heart malfunction, a team of researchers at Tohoku University in Japan went on to investigate the roles of both enzymes in the development of PH associated with heart failure, according to a press release.

ROCK1 and ROCK2 belong to a family of molecules known as the Rho kinases, which play important roles in the process of contraction, motility, proliferation, oxidative stress, and cell death. It is also known that excessive activity of their pathways promotes the development of cardiovascular diseases such as coronary vasospasm, hypertension, PH, and heart failure.

To specifically address the functions of ROCK1 and ROCK2, researchers devised a mouse model of heart failure and PH. They constricted the upper part of the aorta — the artery that transports blood rich in oxygen and nutrients from the left part of the heart — to the rest of the body. This procedure caused chronic pressure overload, mimicking heart failure and PH.

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To check the role of ROCK1 and ROCK2, the team measured the effects of heart failure in two mouse models that were genetically modified to be either defective for ROCK1 or ROCK2 in their heart muscle cells. 

As controls, the team also restricted the aorta in mice with normal levels of ROCK1 and ROCK2.

Looking at these mice models, researchers found that ROCK1 has a protective effect against heart failure and PH, mediated by its inhibitory action over two proteins, cyclophilin A and basigin. These proteins increase oxidative stress in heart muscle cells, leading to their malfunction.

Conversely, ROCK2 exerts a harmful effect, promoting both heart failure and consequent PH by increasing the levels of these two proteins.

As a first attempt to use this knowledge in the discovery of treatments, the team screened for drugs able to inhibit cyclophilin A and basigin in a public chemical database from the Drug Discovery Initiative.

They found a drug called celastrol, with known antioxidant and anti-inflammatory properties. The drug was able to inhibit the expression of cyclophilin A and basigin in the heart and lungs of mice, and reduced heart failure and PH signs (namely, larger-than-normal heart size and abnormal electrocardiography findings).

Thus, by differentially affecting cyclophilin A and basigin levels, “ROCK1 protects and ROCK2 jeopardizes the heart from pressure overload HF [heart failure] with postcapillary PH, for which celastrol may be a promising agent,” the researchers said.

However, the beneficial effects of celastrol may also involve other mechanisms. Therefore, further analyses are required to identify the molecular and cellular targets of celastrol in the treatment of heart failure, the researchers concluded.