Endostatin inhibits bradykinin-induced cardiac contraction

Abstract

.Endogenous fragments of extracellular matrix are known to possess various biological effects. Levels of endostatin, a fragment of collagen type XVIII, increase in certain cardiac diseases, such as cardiac hypertrophy and myocardial infarction. However, the influence of endostatin on cardiac contraction has not been clarified. In the present study, we investigated the effects of endostatin on bradykinin-induced atrial contraction. Isometric contractile force of mouse isolated left atria induced by electrical current pulse was measured. Voltage-dependent calcium current of guinea pig ventricular myocytes was measured by a whole-cell patch-clamp technique. Endostatin (100–1,000 ng/ml) alone treatment had no influence on left atrial contraction. On the other hand, pretreatment with endostatin (300 ng/ml) significantly inhibited bradykinin (1 µM)-induced contraction and voltage-dependent calcium current. These data suggest that endostatin may decrease bradykinin-induced cardiac contraction perhaps through the inhibition of voltage-dependent calcium channel.

New Insights into the Role of Basement Membrane-Derived Matricryptins in the Heart

“…89) We have shown that endostatin inhibits the T-type calcium channel expressed in a ventricular cardiomyocyte from guinea pig, and in a hypertrophied cardiomyocyte from the right ventricle of monocrotalineinduced pulmonary hypertensive rat. 120,121) We also showed that a knockdown of the collagen XVIII (endostatin) gene by siRNA-treatment decreases the survival rate and exacerbates the monocrotaline-induced right ventricular remodeling. 121) Thus, the cardioprotective effect of endostatin might be ex-erted through the inhibition of T-type calcium channel activity.…”

“…120,121) We also showed that a knockdown of the collagen XVIII (endostatin) gene by siRNA-treatment decreases the survival rate and exacerbates the monocrotaline-induced right ventricular remodeling. 121) Thus, the cardioprotective effect of endostatin might be ex-erted through the inhibition of T-type calcium channel activity. Collectively, it is conceivable that basement membranederived matricryptins are likely endogenous cardioprotective peptides.…”

“…[115][116][117][118][119] We have recently shown that endostatin inhibits the T-type calcium ion channel in a ventricular cardiomyocyte from guinea pig, 120) as well as in a cardiomyocyte from hypertrophied right ventricles of monocrotaline-induced pulmonary hypertensive rats. 121) In addition, treatment with small interfering (si)RNA against collagen XVIII decreases the survival rate and exacerbates right ventricular remodeling. 121) Endostatin also has biological effects in the heart, such as the inhibition of bradykinin-induced atrial contractions, per-haps through inhibition of the L-type calcium channel 122) and the stimulation of the proliferation and migration of cardiac fibroblasts through activation of the PI3K/Akt signaling pathway.…”

“…121) In addition, treatment with small interfering (si)RNA against collagen XVIII decreases the survival rate and exacerbates right ventricular remodeling. 121) Endostatin also has biological effects in the heart, such as the inhibition of bradykinin-induced atrial contractions, per-haps through inhibition of the L-type calcium channel 122) and the stimulation of the proliferation and migration of cardiac fibroblasts through activation of the PI3K/Akt signaling pathway. 123) Further study is required to clarify whether endostatin exacerbates or prevents cardiac remodeling.…”

“…114) Moreover, knockdown of the endostatin gene worsens monocrotaline-induced right ventricular remodeling. 121) Thus, increased endostatin during myocardial infarction and pressure overload-induced hypertrophy potentially exerts a cardioprotective effect through the suppression of pathological cardiac remodeling, regardless of its anti-angiogenic effect.…”