Reverse myocardial effects of intermedin in pressure‐overloaded hearts: role of endothelial nitric oxide synthase activity

Abstract

Key points• Intermedin (IMD) is a cardiac endogenous peptide upregulated in several models of heart disease.• We show a depressant effect of IMD 1−47 on contractility of the normal myocardium, mediated by increased nitric oxide (NO) production due to endothelial nitric oxide synthase (eNOS) phosphorylation.• In rat models of cardiac hypertrophy or NO deficiency, IMD 1−47 enhances contractility and hastens relaxation associated with phospholamban phosphorylation.• This opposing response in normal and diseased myocardium is due to impairment of IMD 1−47 -induced eNOS phosphorylation.• The results reveal distinct myocardial effects and subcellular mechanisms for IMD 1−47 in the hypertrophic heart, suggesting a key role of cardiac endothelial dysfunction with potential pathophysiological relevance.Abstract Intermedin (IMD) is a cardiac peptide synthesized in a prepro form, which undergoes a series of proteolytic cleavages and amidations to yield the active forms of 47 (IMD 1−47 ) and 40 amino acids ). There are several lines of evidence of increased IMD expression in rat models of cardiac pathologies, including congestive heart failure and ischaemia; however, its myocardial effects upon cardiac disease remain unexplored. With this in mind, we investigated the direct effects of increasing concentrations of IMD 1−47 (10 −10 to10 −6 M) on contraction and relaxation of left ventricular (LV) papillary muscles from two rat models of chronic pressure overload, one induced by transverse aortic constriction (TAC), the other by nitric oxide (NO) deficiency due to chronic NO synthase inhibition (NG-nitro-L-arginine, L-NAME), and respective controls (Sham and Ctrl). In TAC and L-NAME rats, exogenous administration of IMD 1−47 elicited concentration-dependent positive inotropic and lusitropic effects. By contrast, in Sham and Ctrl rats, IMD 1−47 induced a negative inotropic response without a significant effect on relaxation. Both TAC and L-NAME rats presented LV hypertrophy, elevated LV systolic pressures, preserved systolic function and elevated peroxynitrite levels. In the normal myocardium (Ctrl and Sham), IMD 1−47 induced a 3-fold increase of endothelial nitric oxide synthase (eNOS) phosphorylation at Ser 1177 , indicating enhanced eNOS activity. In TAC and L-NAME rats, eNOS phosphorylation was increased at baseline, and its response to IMD 1−47 was blunted. In addition, the distinct myocardial response to IMD 1−47 was accompanied by distinct subcellular mechanisms. While in Sham rats the addition of IMD 1−47 induced the phosphorylation of cardiac troponin I due to NO/cGMP activation, in TAC rats IMD 1−47 induced phospholamban phosphorylation possibly associated with cAMP/protein kinase A activation. Therefore, we demonstrated for the first time a reversed myocardial response to IMD 1−47 neurohumoral stimulation due to impairment of eNOS activation in TAC and L-NAME rats. These results not only reveal the distinct myocardial effects and subcellular mechanisms for IMD 1−47 in normal and hypertrophic hearts, but also highlig...

Intermedin Suppresses Pressure Overload Cardiac Hypertrophy through Activation of Autophagy

“…As an endogenous multi-functional counter-regulatory peptide in the cardiovascular system, IMD is proposed to activate the intracellular anti-apoptotic effects via the regulation of PKA, PI3K-Akt and mitogen-activated protein kinases (MAPKs) signaling pathways [7], [8]. We observed that IMD, Ang II or ISO incubation alone induced intracellular cAMP production, these results were similar to those reported by Pires [33], Thekkumkara [34], Uchida [35] and their associates, respectively. IMD supplementation remarkably augmented the cAMP contents in H9c2 cells stimulated by Ang II or ISO.…”

Intermedin protects against myocardial ischemia-reperfusion injury in diabetic rats

“…Previously, intermedin has been shown to exert negative inotropic effects in Langendorff-perfused rat hearts, an effect blocked by inhibition of nitric oxide synthesis [57]. Another study demonstrated IMD increased endothelial nitric oxide synthase (eNOS) phosphorylation nearly three-fold at Ser (1177), significantly enhancing eNOS activity [58]. In the current study, IMD administration preserved myocardial NOS activity and cardiac NO levels, suggesting IMD regulates both myocardial NOS activity and NO production.…”

Adrenomedullin 2/intermedin: a putative drug candidate for treatment of cardiometabolic diseases

“…ADM2/IMD 1–47 exerts a direct, positive inotropic effect through the CGRP receptor‐cAMP pathway, in the absence of endothelium (Pires et al , ). Furthermore, in animal models of transverse aortic contraction (TAC) and L‐NAME administration, whose endothelium or eNOS is dysfunctional, the negative inotropic effect of ADM2/IMD 1–47 is abolished (Pires et al , ).…”