Dynamin‐related protein 1 (Drp1)‐mediated diastolic dysfunction in myocardial ischemia‐reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission

Abstract

Mitochondrial fission, regulated by dynamin-related protein-1 (Drp1), is a newly recognized determinant of mitochondrial function, but its contribution to left ventricular (LV) impairment following ischemia-reperfusion (IR) injury is unknown. We report that Drp1 activation during IR results in LV dysfunction and that Drp1 inhibition is beneficial. In both isolated neonatal murine cardiomyocytes and adult rat hearts (Langendorff preparation) mitochondrial fragmentation and swelling occurred within 30 min of IR. Drp1-S637 (serine 637) dephosphorylation resulted in Drp1 mitochondrial translocation and increased mitochondrial fission. The Drp1 inhibitor Mdivi-1 preserved mitochondrial morphology, reduced cytosolic calcium, and prevented cell death. Drp1 siRNA similarly preserved mitochondrial morphology. In Langendorff hearts, Mdivi-1 reduced mitochondrial reactive oxygen species, improved LV developed pressure (92±5 vs. 28±10 mmHg, P<0.001), and lowered LV end diastolic pressure (10±1 vs. 86±13 mmHg, P<0.001) following IR. Mdivi-1 was protective if administered prior to or following ischemia. Because Drp1-S637 dephosphorylation is calcineurin sensitive, we assessed the effects of a calcineurin inhibitor, FK506. FK506 treatment prior to IR prevented Drp1-S637 dephosphorylation and preserved cardiac function. Likewise, therapeutic hypothermia (30°C) inhibited Drp1-S637 dephosphorylation and preserved mitochondrial morphology and myocardial function. Drp1 inhibition is a novel strategy to improve myocardial function following IR.

Regulation of Mitochondrial Dynamics by Dynamin-Related Protein-1 in Acute Cardiorenal Syndrome

“…Protection by mdivi-1 administration against organ dysfunction, including that of the heart and kidney, has already been reported in mouse IR injury models. [15][16][17] In accordance with these reports, we showed protection by mdivi-1 of cardiac injury caused by AKI, addressing the role of Drp1 in the pathophysiology of remote organ injury by AKI. Although pharmacokinetic properties, including the half-life of mdivi-1 in vivo, are not known, several in vivo studies have demonstrated protection by mdivi-1 in different organ IR injury models at 12-48 h after mdivi-1 injection.…”

“…15 Sharp and colleagues showed that Drp1 activation during cardiac IR caused left ventricle dysfunction, which was reversed by Drp1 inhibition. 17 This study demonstrated that renal IR caused cardiac mitochondrial damage via Drp1 activation. This result might support the view that mitochondrial fission by Drp1 activation is a common pathway by which IR injury in one organ causes injury to another remote organ.…”

“…Reportedly, that inhibiting mitochondrial fission protects the heart and kidney from IR injury. [15][16][17] Nevertheless, it remains uncertain whether mitochondrial fission is further involved in the distant organ effects of AKI on the heart. This study was undertaken to clarify the role of mitochondrial dynamics in AKI-induced cardiac injury, namely acute renocardiac syndrome, using a mouse renal IR model.…”

Mitochondrial Ca 2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

“…Cells were put into the culture incubator overnight (≥16 hours). Images were taken with excitation/emission at 485/520 nm 30. The average fluorescence density (mitochondrial green fluorescent protein fluorescence normalized by area) was used to analyze data.…”

Dynamin Functions and Ligands: Classical Mechanisms Behind

“…Drp1 activation during ischemia reperfusion results in LV dysfunction, implying that Drp1 inhibition is beneficial for heart activity (Sharp et al, 2014). Cardiac myopathy is linked to a decreased level of OPA1.…”