Creatine kinase, energy reserve, and hypertension: from bench to bedside
We hypothesized that human variation in the activity of the ATP regenerating enzyme creatine kinase (CK) activity affects hypertension and cardiovascular disease risk. CK is tightly bound close to ATP-utilizing enzymes including Ca2+-ATPase, myosin ATPase, and Na+/K+-ATPase, where it rapidly regenerates ATP from ADP, H+, and phosphocreatine. Thus, relatively high CK was thought to enhance ATP-demanding processes including resistance artery contractility and sodium retention, and reduce ADP-dependent functions. In a series of studies of our group and others, CK was linked to hypertension and bleeding risk. Plasma CK after rest, used as a surrogate measure for tissue CK, was associated with high blood pressure and failure of antihypertensive therapy in case-control and population studies. Importantly, high tissue CK preceded hypertension in animal models and in humans, and human vascular tissue CK gene expression was strongly associated with clinical blood pressure. In line with this, CK inhibition substantially reduced the contractility of human resistance arteries ex vivo. We also presented evidence that plasma CK reduced ADP-dependent platelet aggregation. In subsequent intervention studies, the oral competitive CK inhibitor beta-guanidinopropionic acid (GPA) reduced blood pressure in spontaneously hypertensive rats (SHRs), and a 1-week trial of sub-therapeutic dose GPA in healthy men was uneventful. Thus, based on theoretical concepts, evidence was gathered in laboratory, case-control, and population studies that high CK is associated with hypertension and with bleeding risk, potentially leading to a new mode of cardiovascular risk reduction with CK inhibition.