Development of Novel Therapies for Cardiovascular Diseases by Clinical Application of Basic Research

Abstract

Cyclophilin A (CyPA) is secreted from vascular smooth muscle cells, inflammatory cells, activated platelets, and cardiac fibroblasts in response to oxidative stress. Excessive and continuous activation of the RhoA/Rho-kinase system promotes the secretion of CyPA, resulting in the development of multiple cardiovascular diseases. Basigin (Bsg), a transmembrane glycoprotein that activates matrix metalloproteinases, is an extracellular receptor for CyPA that promotes cell proliferation and inflammation. Thus, the CyPA/Bsg system is potentially a novel therapeutic target for cardiovascular diseases. Importantly, plasma CyPA levels are increased in patients with coronary artery disease, abdominal aortic aneurysms, pulmonary hypertension, and heart failure. Moreover, plasma CyPA levels can predict all-cause death in patients with coronary artery disease and pulmonary hypertension. Additionally, plasma soluble Bsg levels are increased and predict all-cause death in patients with heart failure, suggesting that CyPA and Bsg are novel biomarkers for cardiovascular diseases. To discover further novel molecules targeting the CyPA/Bsg system, high-throughput screening of compounds found molecules that ameliorate the development of cardiovascular diseases. In addition to CyPA and Bsg, novel therapeutic targets and their inhibitors for patients with pulmonary arterial hypertension have been recently screened and identified. Ultimately, the final goal is to develop novel biomarkers and medications that will be useful for improving the prognosis and quality of life in patients with cardiovascular diseases.

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

“…Endothelial cells (ECs) are involved in the maintenance of pulmonary vascular homeostasis by releasing paracrine factors and modulating the permeability of the endothelial barrier to leukocytes [ 23 , 51 ]. EC dysfunction is associated with progression of PH, especially in the generation of plexiform vascular lesions [ 33 ].…”

Gentiopicroside Produces Endothelium-Independent Vasodilation by Deactivating the PI3K/Akt/Rho-Kinase Pathway in Isolated Rat Thoracic Aorta

“…Hypertension, angina pectoris, and acute coronary syndrome are usually accompanied by the pathological characters of decreased vasodilation ability and enhanced vasoconstriction that may lead to vessel occlusion and insufficient blood supply to important organs and tissues, which serve as the main major risk factors for cardiovascular diseases [27]. Therefore, improving the vasodilation function of patients is considered an effective method for the prevention and treatment of cardiovascular diseases [28]. To date, rat thoracic aortic rings are used by many researchers as classical models to investigate the vasorelaxation effects of drugs.…”

Serendipity: How the search for meaning of serum uric acid might lead to the repurposing of an old drug in patients with cardiovascular disease

“…It is an exciting time in athero-biology with an increasing ability to target specific cellular pathways known to be critical in the development and progression of atherosclerosis; however, by their very nature any new developments will likely remain decades away from the bedside. 20 In the interim, researchers and funding bodies should be bold and not miss the opportunity to explore the potential of older medication with known long-term safety if there is sufficient reason to do so. In the case of allopurinol, it is interesting to consider how the measurement of sUA, a non-specific prognostic biomarker in search of clinical relevance, might serendipitously lead to the repurposing of an old drug for a most worthy purpose.…”