Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice

Tissue kallikrein is a serine protease thought to be involved in the genera tion of bioactive peptide kinins in many organs like the kidneys, colon, sa livary glands, pancreas, and blood vessels. Low renal synthesis and urinary excretion of tissue kallikrein have been repeatedly linked to hypertension in animals and humans, but the exact role of the protease in cardiovascula r function has not been established largely because of the lack of specific inhibitors. This study demonstrates that mice lacking tissue kallikrein ar e unable to generate significant levels of kinins in most tissues and devel op cardiovascular abnormalities early in adulthood despite normal blood pre ssure. The heart exhibits septum and posterior wall thinning and a tendency to dilatation resulting in reduced left ventricular mass. Cardiac function estimated in vivo and in vitro is decreased both under basal conditions an d in response to beta -adrenergic stimulation. Furthermore, flow-induced va sodilatation is impaired in isolated perfused carotid arteries, which expre ss, like the heart, low levels of the protease. These data show that tissue kallikrein is the main kinin-generating enzyme in vivo and that a function al kallikrein-kinin system is necessary for normal cardiac and arterial fun ction in the mouse. They suggest that the kallikrein-kinin system could be involved in the development or progression of cardiovascular diseases.