Heparanase: A Novel Therapeutic Target for the Treatment of Atherosclerosis

Abstract

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and its management places a huge burden on healthcare systems through hospitalisation and treatment. Atherosclerosis is a chronic inflammatory disease of the arterial wall resulting in the formation of lipid-rich, fibrotic plaques under the subendothelium and is a key contributor to the development of CVD. As such, a detailed understanding of the mechanisms involved in the development of atherosclerosis is urgently required for more effective disease treatment and prevention strategies. Heparanase is the only mammalian enzyme known to cleave heparan sulfate of heparan sulfate proteoglycans, which is a key component of the extracellular matrix and basement membrane. By cleaving heparan sulfate, heparanase contributes to the regulation of numerous physiological and pathological processes such as wound healing, inflammation, tumour angiogenesis, and cell migration. Recent evidence suggests a multifactorial role for heparanase in atherosclerosis by promoting underlying inflammatory processes giving rise to plaque formation, as well as regulating lesion stability. This review provides an up-to-date overview of the role of heparanase in physiological and pathological processes with a focus on the emerging role of the enzyme in atherosclerosis.

Heparanase Modulates Chromatin Accessibility

“…Collectively, we propose that heparanase may function as an epigenetic marker, modulating innate immunity and other cellular functions, in part by controlling gene expression. Given that heparanase is a well-recognized target for inhibition of cancer progression and inflammation [ 43 , 47 ], our findings further strengthen this notion by broadening the multitasking molecular function of the heparanase gene and protein.…”

Serum proteome profiling reveals heparanase as a candidate biomarker for chronic thromboembolic pulmonary hypertension

“…Recent evidence suggests a multifactorial role for HPSE in atherosclerosis by promoting underlying inflammatory processes giving rise to plaque formation, as well as regulating lesion stability. 21 HPSE also plays a procoagulant role in several arterial and venous thrombotic diseases. 22 The subsequent study demonstrated that elevated HPSE levels were associated with higher thrombus load and rates of thromboembolic complications.…”

Heparanase—A single protein with multiple enzymatic and nonenzymatic functions

“… 11 , 12 , 97 While most studies emphasize the involvement of heparanase in cancer and inflammation, other pathologies were investigated. Among these are diabetes, 74 , 75 diabetic complications (i.e., diabetic nephropathy, diabetic cardiomyopathy), 76 , 77 kidney dysfunction, 182 fibrosis, 78 , 183 inflammatory disorders (i.e., neuroinflammation, pancreatitis, ulcerative colitis, arthritis, sepsis), 59 , 60 , 184 , 185 amyloidosis, 61 atherosclerosis, 66 , 68 , 69 , 70 viral diseases, 96 , 97 and other pathologies. 11 , 12 , 97 Heparanase accomplishes all these by exerting both enzymatic and nonenzymatic functions that are mostly HS‐dependent yet in some cases are HS‐independent.…”