Human tissue kallikrein in the treatment of acute ischemic stroke

Abstract

Acute ischemic stroke (AIS) remains a major cause of death and disability throughout the world. The most severe form of stroke results from large vessel occlusion of the major branches of the Circle of Willis. The treatment strategies currently available in western countries for large vessel occlusion involve rapid restoration of blood flow through removal of the offending blood clot using mechanical or pharmacological means (e.g. tissue plasma activator; tPA). This review assesses prospects for a novel pharmacological approach to enhance the availability of the natural enzyme tissue kallikrein (KLK1), an important regulator of local blood flow. KLK1 is responsible for the generation of kinins (bradykinin and kallidin), which promote local vasodilation and long-term vascularization. Moreover, KLK1 has been used clinically as a direct treatment for multiple diseases associated with impaired local blood flow including AIS. A form of human KLK1 isolated from human urine is approved in the People’s Republic of China for subacute treatment of AIS. Here we review the rationale for using KLK1 as an additional pharmacological treatment for AIS by providing the biochemical mechanism as well as the human clinical data that support this approach.

The role of genomics and genetics in pulmonary arterial hypertension

“…In humans, polymorphism in the regulatory region of KLK1 is responsible for significant differences in hK1 expression and susceptibility to systemic hypertension 83, 84 . These findings suggested that KLK1 pathway might be a potential drug target; indeed, recombinant KLK1 treatment has been shown to improve the recovery in acute ischemic stroke by augmenting penumbral blood flow and suppressing inflammation 74 .…”

“…KLK1 74 is a component of the kallikrein-kinin system (KKS) implicated in the homeostasis of the cardiovascular, renal and central nervous system 75, 76 . The KKS comprises kallikreins, kininogens, kinins, kinin receptors and kininases (angiotensin-converting enzyme, ACE is the most important kinin-degrading enzyme in the cardiovascular system) 77 .…”

The Emerging Role of Renal Tubular Epithelial Cells in the Immunological Pathophysiology of Lupus Nephritis

“…The inducible expression of KLK1 in RTECs has also been shown to downmodulate local pathological reactions and confer renoprotection in mice with spontaneous LN ( 73 ). Further preclinical studies of KLK1 may support the evaluation of DM199, a recombinant form of human KLK1 currently in acute ischemic stroke clinical trials ( 74 ), for the treatment of LN.…”

Heparin Blocks the Inhibition of Tissue Kallikrein 1 by Kallistatin through Electrostatic Repulsion

“…In the human KLKs family, only KLK1 could release kinin from low molecular weight kininogen, while the other KLKs possess greatly reduced or no kininogen cleavage activity [ 16 ]. KLK1 is a key member of the kallikrein-kinin system that initiates and maintains vasodilation in mammalian system and its deficits are associated with cardiovascular and end-organ pathology [ 18 ]. KLK1 replenishment therapy is widely used in Asia for the treatment of diseases such as acute ischemic stroke [ 18 ].…”

“…KLK1 is a key member of the kallikrein-kinin system that initiates and maintains vasodilation in mammalian system and its deficits are associated with cardiovascular and end-organ pathology [ 18 ]. KLK1 replenishment therapy is widely used in Asia for the treatment of diseases such as acute ischemic stroke [ 18 ].…”