This novel therapy involves using valosin-containing protein (VCP) to prevent or treat ischemic and pressure overload-induced heart disease. Inactivation and reduced VCP expression are highly associated with multiple cardiac diseases. Overexpression of VCP in the heart has been found to reduce infarct size during ischemia-reperfusion injury and also protect against pressure overload-induced cardiomyopathy and heart failure (HF). VCP protects against these diseases through comprehensive mechanisms, such as promoting cardiomyocyte survival signaling, preserving mitochondrial energy production, preventing mPTP opening, and inhibiting stress-induced cardiac inflammatory response. Studies by University of Arizona researchers found that increasing VCP in the heart protects against ischemia damage and prevents reperfusion injury, indicating a dual-role therapeutic strategy. Researchers also identified that insufficient VCP in the heart accelerates cardiac dysfunction and leads to HF under pressure overload conditions, such as hypertension. Conversely, overexpression of VCP in cardiomyocytes significantly reduces hypertension-associated cardiomyopathy and prevents HF under prolonged pressure overload, through a previously unrecognized mechanism, highlighting its promising therapeutic potential. Based on these findings, researchers are developing a mechanism-based therapy to deliver VCP protein into the heart to protect against injury caused by both ischemia and reperfusion. Background: Ischemic heart disease (or heart attack) is a leading acute cause of death worldwide. Although reperfusion therapies such as Percutaneous Coronary Intervention are lifesaving for patients with acute myocardial ischemia (AMI), they can trigger reperfusion injury leading to adverse remodeling and heart failure. In addition, many patients with acute myocardial ischemia cannot receive immediate reperfusion therapies due to the lack of technique, missing the surgery window, or other complications. These limitations highlight the need for targeted strategies to mitigate I/R injury and improve long-term outcomes for AMI patients. Applications: Increasing VCP in the heart to treat the following diseases: Ischemic heart disease Reperfusion injury after restoration of blood flow in ischemia Pressure overload heart failure (hypertensive or aortic stenosis) Aging-related heart disease therapeutics Heart disease with valosin-containing protein deficiency
Advantages: Mechanism-based therapy targets pathologies of ischemic/heart diseases, with less off-target effects A new therapy for ischemic patients who fail the reperfusion therapy A combined therapy for the patients who have received reperfusion therapy, to improve cardiac outcome Offers a preventive approach for the patient at risk of ischemic disease Offers a preventive or therapeutic approach for patients under pressure overload Expansion to treat other types of heart diseases associated with VCP deficiency Reduced the mortality of ischemia and pressure overload in the heart