Protein kinases in cardiovascular diseases

Cardiovascular disease (CVD) is the leading cause of death worldwide, claiming 17.9 million lives annually—more than cancer or respiratory illness, according to the World Health Organization. For researchers, solving the puzzle of how CVD develops and progresses is critical to saving lives. A 2022 review by Jiawen Chen, Yafei Li, and colleagues from the Department of Cardiology at The First Affiliated Hospital of Nanjing Medical University reveals a key piece of that puzzle: protein kinases—tiny cellular “switches” that control nearly every function of heart cells, from pumping blood to repairing damage.

What are protein kinases?

Protein kinases are enzymes that add chemical tags (called phosphates) to other proteins. This process, phosphorylation, acts like a light switch: it turns protein activity on or off. In the heart, kinases regulate everything from calcium levels (essential for muscle contraction) to energy use, cell growth, and even cell death. Humans have over 500 protein kinases, but only a subset are critical to heart health. The review focuses on three main types—serine/threonine kinases, tyrosine kinases, and dual-specificity kinases—and how their misregulation fuels diseases like heart failure, atherosclerosis, and arrhythmias.

Protein kinases in heart failure: Balancing growth and damage

Heart failure occurs when the heart can’t pump enough blood to meet the body’s needs. A common precursor is cardiac hypertrophy—enlarged heart cells that eventually lose function. Protein kinases are central to this process:

AKT and mTOR: These kinases drive excess protein synthesis in heart cells, making them grow too large.
CaMKII: Overactive CaMKII disrupts calcium balance (critical for contraction) and breaks down a protein called UBE2T, leading to DNA damage in heart cells.
AMPK: A “protective” kinase, AMPK cleans up damaged mitochondria (the cell’s power plants) and reduces harmful sugar modifications (O-GlcNAcylation) on proteins, slowing heart failure progression.

Research suggests drugs targeting these kinases—like rapamycin (which blocks mTOR) or AMPK activators—could reverse hypertrophy and improve heart function.

Atherosclerosis: Inflammation, plaque, and kinases

Atherosclerosis—hardened arteries from fatty plaque buildup—is the leading cause of heart attacks and strokes. Protein kinases drive two key processes:

Macrophage polarization: Immune cells called macrophages can be “pro-inflammatory” (M1, which worsens plaque) or “healing” (M2, which reduces it). The AKT pathway controls this switch: too much AKT2 pushes macrophages to M1, while AKT1 promotes M2.
Vessel wall damage: The p38 kinase increases the stickiness of blood vessel walls, letting more immune cells cling and grow. Studies show hydroxytyrosol (a compound in olive oil) blocks p38, reducing plaque in animals.

The review highlights that balancing kinase activity could stop plaque before it causes damage.

Myocardial infarction: Regenerating dead heart cells

After a heart attack (myocardial infarction, MI), dead heart cells can’t regenerate—until researchers looked at protein kinases. Unlike most adult cells, heart cells stop dividing after childhood. But kinases like CDK2 and ERBB2 can jumpstart cell division:

A study in mice found activating CHK1 kinase boosted heart cell proliferation and repair after MI.
Kinases like ROCK improve stem cell transplant success by helping new cells stick to the heart.

These findings offer hope for “in situ” heart regeneration—growing new cells where they’re needed most.

Hypertension: Overactive vessels and kinase control

High blood pressure (hypertension) and pulmonary arterial hypertension (PAH) occur when blood vessels constrict too much or grow abnormally. Protein kinases are key drivers:

ROCK: This kinase makes smooth muscle cells in vessels contract too much, raising blood pressure. It also reduces nitric oxide (a vessel relaxant), worsening the problem.
ERK and AKT: These kinases promote abnormal vessel growth in PAH.

Drugs like resveratrol (found in red wine) block ERK and AKT, reducing vessel thickening in animal studies. For humans, ROCK inhibitors like fasudil have relieved refractory coronary spasms—proof that kinase targeting works in real patients.

Arrhythmias: Calcium leaks and kinase guards

Arrhythmias—irregular heartbeats—are often caused by faulty calcium regulation. The CaMKII kinase is a major culprit: it overactivates calcium channels in the heart’s sarcoplasmic reticulum (a storage compartment), causing “leaks” that trigger abnormal beats.

AMPK: A protective kinase, AMPK stabilizes ion channels and reduces calcium leaks, lowering the risk of atrial fibrillation (AF), the most common sustained arrhythmia.
Common drugs like metformin (for diabetes) work in part by activating AMPK, explaining their anti-arrhythmic effects.

Research into CaMKII inhibitors—like RA306—could offer new treatments for AF and other rhythm disorders.

Cardiomyopathies: Genetic faults and kinase fixes

Hypertrophic (HCM) and dilated (DCM) cardiomyopathies—genetic heart muscle diseases—are linked to kinase misregulation:

HCM: The PI3K-AKT-YAP pathway creates a feedback loop that makes heart cells grow too large. Drugs blocking MEK (a kinase in this pathway) have improved heart function in small trials.
DCM: Mutations in the LMNA gene activate ERK and JNK kinases, disrupting heart muscle structure. Kinase inhibitors like those targeting ERK could slow DCM progression.

Clinical perspective: From lab to patient

The review isn’t just theoretical—it’s moving to clinics:

Ruboxistaurin: A PKC inhibitor, it improved heart function in pig models of heart failure.
Fasudil: A ROCK inhibitor, it relieves refractory coronary spasms in patients.
Losmapimod: A p38 inhibitor, though not effective for acute MI, is being tested in other CVDs.

But challenges remain:

Targeted delivery: Getting drugs to heart cells without harming other organs.
Kinase subtypes: Some kinases (like AKT) have “good” and “bad” subtypes—blocking the wrong one could backfire.

Conclusion: Protein kinases as the future of CVD treatment

Chen and colleagues’ review makes clear: protein kinases are not just “molecular switches”—they’re master regulators of heart health. From regenerating dead heart cells to stopping plaque growth, these enzymes offer a new frontier in CVD therapy. While more research is needed to refine treatments and avoid side effects, the promise is undeniable: targeting protein kinases could turn CVD from a leading cause of death to a manageable condition.

Original study: Chen J, Li Y, Du C, Wei T, Shan T, Wang L. Protein kinases in cardiovascular diseases. Chin Med J 2022;135:557–570. doi: doi.org/10.1097/CM9.0000000000001870

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