Novel Insight into the Role of Endoplasmic Reticulum Stress in the Pathogenesis of Myocardial Ischemia-Reperfusion Injury

Abstract

Impaired function of the endoplasmic reticulum (ER) is followed by evolutionarily conserved cell stress responses, which are employed by cells, including cardiomyocytes, to maintain and/or restore ER homeostasis. ER stress activates the unfolded protein response (UPR) to degrade and remove abnormal proteins from the ER lumen. Although the UPR is an intracellular defense mechanism to sustain cardiomyocyte viability and heart function, excessive activation initiates ER-dependent cardiomyocyte apoptosis. Myocardial ischemia/reperfusion (I/R) injury is a pathological process occurring during or after revascularization of ischemic myocardium. Several molecular mechanisms contribute to the pathogenesis of cardiac I/R injury. Due to the dual protective/degradative effects of ER stress on cardiomyocyte viability and function, it is of interest to understand the basic concepts, regulatory signals, and molecular processes involved in ER stress following myocardial I/R injury. In this review, therefore, we present recent findings related to the novel components of ER stress activation. The complex effects of ER stress and whether they mitigate or exacerbate myocardial I/R injury are summarized to serve as the basis for research into potential therapies for cardioprotection through control of ER homeostasis.

RETRACTED: Mitofusin-2 Enhances Mitochondrial Contact With the Endoplasmic Reticulum and Promotes Diabetic Cardiomyopathy

“…ROS are mainly generated by mitochondrial respiratory complexes I and III, and higher calcium concentrations are associated with greater ROS production in the mitochondria ( Lindner et al, 2020 ; Zhang J. et al, 2020 ). The mitochondrial morphology is also altered by mitochondria–ER contact, with increased contact promoting mitochondrial fission and reduced contact enhancing mitochondrial fusion ( Li et al, 2020 ; Wang et al, 2020e ; Zhu and Zhou, 2021 ). These observations led us to wonder whether hyperglycemia-induced cardiomyocyte apoptosis could be due to abnormal mitochondria–ER contact.…”

RETRACTED: Abnormal Mitochondria-Endoplasmic Reticulum Communication Promotes Myocardial Infarction

“…In clinical practice, thrombolytic therapy and/or percutaneous coronary interaction surgery are the standard methods of enhancing cardiomyocyte survival in patients with myocardial infarction ( Gori et al, 2020 ; Kleinbongard, 2020 ; Watson et al, 2020 ). Despite advances in the treatment of myocardial infarction, the molecular pathways underlying ischemia-induced cardiomyocyte death are not fully understood ( Wang et al, 2020b , c ; Wang and Zhou, 2020 ; Zhu and Zhou, 2021 ). Determining the upstream signals of mitochondria-dependent cardiomyocyte death will enable the development of therapeutic approaches to improve cardiomyocyte survival during or after myocardial infarction ( Hillmeister et al, 2020 ; Pflüger-Müller et al, 2020 ).…”

“…Mitochondrial division depends on the cooperation between mitochondrial fission factors and the endoplasmic reticulum (ER) ( Chang et al, 2021 ; Zhu and Zhou, 2021 ). The ER provides anchoring strength to promote mitochondrial contraction, while mitochondrial fission factors such as mitochondrial fission 1 (Fis1), dynamin-related protein 1 (Drp1), mitochondrial fission factor (Mff), mitochondrial dynamics protein of 49 kDa (Mid49) and mitochondrial dynamics protein of 51 kDa (Mid51) perform the contraction ( Zhou et al, 2018b ; Lobo-Gonzalez et al, 2020 ).…”

MKP-1 Overexpression Reduces Postischemic Myocardial Damage through Attenuation of ER Stress and Mitochondrial Damage

“…Interestingly, these molecular events are closely associated with mitochondrial dysfunction and ER stress [20]. ER is an important organelle that regulates calcium homeostasis, protein synthesis and processing, and protein transport in eukaryotic cells [21]. An excessive accumulation of unfolded or misfolded proteins or calcium ion disbalance in ER leads to ER dysfunction, resulting in cardiomyocyte death [22].…”