420
H. Jin
14.3.2.1 Myocardial Infarction
Cardiovascular diseases (CVD) remain the leading cause of death globally, acute
myocardial infarction (AMI) accounts for one-third of deaths of CVD.
Circulating angiotensin II (Ang II) is a powerful vasoconstrictor, its elevation
can lead to chronic deterioration of post-myocardial Infarction (MI) cardiac function
caused by the cardiac afterload increase. Chymase is a chymotrypsin-like serine
protease, playing important roles in the regulation of local Ang II formation in human
cardiovascular tissues. Thus, inhibiting chymase activity is a potential therapy in
acute cardiac failure.
Chymases [74] are mainly expressed in mast cells (MCs),fibroblasts, vascular
endothelial cells, and granulocytes. It is well known that chymases participate in
the process of inflammation, allergy, angiogenesis, oncogenesis, remodeling of the
extracellular matrix of the connective tissue, and changes in organ histoarchitectonics [75]. A growing number of studies suggest a significant role of chymase as the
Ang II forming enzyme from either Ang I or directly from Ang-(1-12) [76–78].In
heart tissues, chymase is responsible for Ang II formation (80–90%) in cardiovascular tissues and cells obtained either from human subjects or animal models [79].
Chymase inhibitor as a target therapy for cardiovascular disease has already been in
preclinical studies. Most of the existing chymase inhibitors are peptides. Jin et al.
[80] constructed a new chymase-specific inhibitory RNA aptamer (HA28) against
hamster chymase, they examined its treatment effects in a hamster left coronary artery
(LCA) ligation model. After 14-day treatment, HA28 significantly improved the ratio
of early to late ventricular filling velocities after myocardial infarction and reduced
the mortality rate (8%; p < 0.05, vehicle versus HA28). This study provides the first
evidence for using a single-stranded RNA chymase-specific inhibitor aptamer in the
treatment of acute heart failure caused by myocardial infarction, indicating that the
inhibition of chymase activity by HA28, even 1 day after MI, improved the outcome
following MI.
Von Willebrand Factor (VWF) is a blood glycoprotein. It plays a pivotal role in
platelet adhesion and aggregation at sites of high shear rates, e.g., in coronary arteries
which have stenotic or ruptured atherosclerotic plaque lesions [81, 82]. Typically,
VWF rises during the course of acute coronary syndromes (ACS). The level of VWF
can be used as an independent predictor of clinical adverse outcome, especially in
patient with pre-existing vascular disease [83, 84].
The Anti-VWF aptamer ARC1779 binds the A1 domain of activated VWF and
inhibits its interaction with the GPIb receptor on platelets. ARC1779 produced
dose—and concentration-dependent inhibition of VWF activity and platelet function
in a phase I trial in healthy volunteers [85]. Spiel et al. [86] recruited 80 patient (40
patients with AMI on standard treatment, 20 young controls, and 20 elderly control)
to study the ex vivo dose response curves for ARC1779 on VWF activity, sheardependent platelet function, and agonist-induced platelet aggregation. AMI patients
displayed twofold increased plasma levels of VWF activity as compared to controls.
ARC1779 inhibitedVWF activity (IC90: 3–4 mg/mL) and shear-dependent platelet
H. Jin
14.3.2.1 Myocardial Infarction
Cardiovascular diseases (CVD) remain the leading cause of death globally, acute
myocardial infarction (AMI) accounts for one-third of deaths of CVD.
Circulating angiotensin II (Ang II) is a powerful vasoconstrictor, its elevation
can lead to chronic deterioration of post-myocardial Infarction (MI) cardiac function
caused by the cardiac afterload increase. Chymase is a chymotrypsin-like serine
protease, playing important roles in the regulation of local Ang II formation in human
cardiovascular tissues. Thus, inhibiting chymase activity is a potential therapy in
acute cardiac failure.
Chymases [74] are mainly expressed in mast cells (MCs),fibroblasts, vascular
endothelial cells, and granulocytes. It is well known that chymases participate in
the process of inflammation, allergy, angiogenesis, oncogenesis, remodeling of the
extracellular matrix of the connective tissue, and changes in organ histoarchitectonics [75]. A growing number of studies suggest a significant role of chymase as the
Ang II forming enzyme from either Ang I or directly from Ang-(1-12) [76–78].In
heart tissues, chymase is responsible for Ang II formation (80–90%) in cardiovascular tissues and cells obtained either from human subjects or animal models [79].
Chymase inhibitor as a target therapy for cardiovascular disease has already been in
preclinical studies. Most of the existing chymase inhibitors are peptides. Jin et al.
[80] constructed a new chymase-specific inhibitory RNA aptamer (HA28) against
hamster chymase, they examined its treatment effects in a hamster left coronary artery
(LCA) ligation model. After 14-day treatment, HA28 significantly improved the ratio
of early to late ventricular filling velocities after myocardial infarction and reduced
the mortality rate (8%; p < 0.05, vehicle versus HA28). This study provides the first
evidence for using a single-stranded RNA chymase-specific inhibitor aptamer in the
treatment of acute heart failure caused by myocardial infarction, indicating that the
inhibition of chymase activity by HA28, even 1 day after MI, improved the outcome
following MI.
Von Willebrand Factor (VWF) is a blood glycoprotein. It plays a pivotal role in
platelet adhesion and aggregation at sites of high shear rates, e.g., in coronary arteries
which have stenotic or ruptured atherosclerotic plaque lesions [81, 82]. Typically,
VWF rises during the course of acute coronary syndromes (ACS). The level of VWF
can be used as an independent predictor of clinical adverse outcome, especially in
patient with pre-existing vascular disease [83, 84].
The Anti-VWF aptamer ARC1779 binds the A1 domain of activated VWF and
inhibits its interaction with the GPIb receptor on platelets. ARC1779 produced
dose—and concentration-dependent inhibition of VWF activity and platelet function
in a phase I trial in healthy volunteers [85]. Spiel et al. [86] recruited 80 patient (40
patients with AMI on standard treatment, 20 young controls, and 20 elderly control)
to study the ex vivo dose response curves for ARC1779 on VWF activity, sheardependent platelet function, and agonist-induced platelet aggregation. AMI patients
displayed twofold increased plasma levels of VWF activity as compared to controls.
ARC1779 inhibitedVWF activity (IC90: 3–4 mg/mL) and shear-dependent platelet