Loss of Apelin Exacerbates Myocardial Infarction Adverse Remodeling and Ischemia‐reperfusion Injury: Therapeutic Potential of Synthetic Apelin Analogues

Abstract

BackgroundCoronary artery disease leading to myocardial ischemia is the most common cause of heart failure. Apelin (APLN), the endogenous peptide ligand of the APJ receptor, has emerged as a novel regulator of the cardiovascular system.Methods and ResultsHere we show a critical role of APLN in myocardial infarction (MI) and ischemia‐reperfusion (IR) injury in patients and animal models. Myocardial APLN levels were reduced in patients with ischemic heart failure. Loss of APLN increased MI‐related mortality, infarct size, and inflammation with drastic reductions in prosurvival pathways resulting in greater systolic dysfunction and heart failure. APLN deficiency decreased vascular sprouting, impaired sprouting of human endothelial progenitor cells, and compromised in vivo myocardial angiogenesis. Lack of APLN enhanced susceptibility to ischemic injury and compromised functional recovery following ex vivo and in vivo IR injury. We designed and synthesized two novel APLN analogues resistant to angiotensin converting enzyme 2 cleavage and identified one analogue, which mimicked the function of APLN, to be markedly protective against ex vivo and in vivo myocardial IR injury linked to greater activation of survival pathways and promotion of angiogenesis.ConclusionsAPLN is a critical regulator of the myocardial response to infarction and ischemia and pharmacologically targeting this pathway is feasible and represents a new class of potential therapeutic agents.

Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction

“…In line with these findings, we observe that the lack of apelin induces a deleterious microenvironment characterized by an increase in inflammatory mediators and immune cell infiltration after MI. Although apelin-deficient mice have normal cardiac function, these mice exhibit a susceptibility to heart failure and reduced heart contractility in aging mice (40,41). Lymphatic vessel dysfunction associated with the accumulation of immune cells in cardiac tissue could in part explain the increase of susceptibility to MI in apelin-deficient mice.…”

Patient healthcare trajectory. An essential monitoring tool: a systematic review

“…cardiac or renal, but also to the various treatments and therapies. In response to Q5, T2 was thus related to research: in disease studies [30][31][32][33][34][35][36][37], to compare care and coding [38][39][40], but also in monitoring of patients over time and the survival rate [31,[41][42][43][44]. Survival rate forms part of a trajectory concept.…”

“…There is also emergency management before hospital admission, including transport and first aid. Then there is care at admission, medication management [44] and associated costs-here the trajectory concept emerges. There is also an aspect regarding the effectiveness of the measures implemented [46][47][48][49][50][51][52] and the different treatments [53][54][55].…”

Resistin-induced cardiomyocyte hypertrophy is inhibited by apelin through the inactivation of extracellular signal-regulated kinase signaling pathway in H9c2 embryonic rat cardiomyocytes

“…Apelin is synthesized as a 77-amino acid peptide processed into various C-terminal fragments, including apelin-36, -19, -17, -13, -12, and [Pyr1]-apelin-13. Apelin-13 is the most stable amongst Resistin-induced cardiomyocyte hypertrophy is inhibited by apelin through the inactivation of extracellular signal-regulated kinase signaling pathway in H9c2 embryonic rat cardiomyocytes them (20,21). Deficiency of apelin exacerbates MI adverse remodeling and ischemia-reperfusion (I/R) injury (21).…”

“…Apelin-13 is the most stable amongst Resistin-induced cardiomyocyte hypertrophy is inhibited by apelin through the inactivation of extracellular signal-regulated kinase signaling pathway in H9c2 embryonic rat cardiomyocytes them (20,21). Deficiency of apelin exacerbates MI adverse remodeling and ischemia-reperfusion (I/R) injury (21). Treatment with apelin promotes myocardial angiogenesis and improves cardiac function in post-MI mice (22).…”