Impaired oxidative metabolism and calcium mishandling underlie cardiac dysfunction in a rat model of post-acute isoproterenol-induced cardiomyopathy

Abstract

Stress-induced cardiomyopathy, triggered by acute catecholamine discharge, is a syndrome characterized by transient, apical ballooning linked to acute heart failure and ventricular arrhythmias. Rats receiving an acute isoproterenol (ISO) overdose (OV) suffer cardiac apex ischemia-reperfusion damage and arrhythmia, and then undergo cardiac remodeling and dysfunction. Nevertheless, the subcellular mechanisms underlying cardiac dysfunction after acute damage subsides are not thoroughly understood. To address this question, Wistar rats received a single ISO injection (67 mg/kg). We found in vivo moderate systolic and diastolic dysfunction at 2 wk post-ISO-OV; however, systolic dysfunction recovered after 4 wk, while diastolic dysfunction worsened. At 2 wk post-ISO-OV, cardiac function was assessed ex vivo, while mitochondrial oxidative metabolism and stress were assessed in vitro, and Ca(2+) handling in ventricular myocytes. These were complemented with sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), phospholamban (PLB), and RyR2 expression studies. Ex vivo, basal mechanical performance index (MPI) and oxygen consumption rate (MVO2) were unchanged. Nevertheless, upon increase of metabolic demand, by β-adrenergic stimulation (1-100 nM ISO), the MPI versus MVO2 relation decreased and shifted to the right, suggesting MPI and mitochondrial energy production uncoupling. Mitochondria showed decreased oxidative metabolism, membrane fragility, and enhanced oxidative stress. Myocytes presented systolic and diastolic Ca(2+) mishandling, and blunted response to ISO (100 nM), and all these without apparent changes in SERCA, PLB, or RyR2 expression. We suggest that post-ISO-OV mitochondrial dysfunction may underlie decreased cardiac contractility, mainly by depletion of ATP needed for myofilaments and Ca(2+) transport by SERCA, while exacerbated oxidative stress may enhance diastolic RyR2 activity.

Vagal nerve stimulation improves mitochondrial dynamics via an M3 receptor/CaMKKβ/AMPK pathway in isoproterenol‐induced myocardial ischaemia

“…Furthermore, ISO reduced hemodynamic parameters (MAP, LVDP, and AEdP/dt max ) and increased the infarct area. Taken together, ISO induces an acute MI and, additionally, induced mitochondrial dysfunction-including impaired oxidative metabolism, calcium mishandling [42], decreased mitochondrial bioenergetics and enhanced oxidative stress [43], but the effects on mitochondrial dynamics were rare.…”

Molecular pathways of oestrogen receptors and β‐adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

“…Intracellular Ca 2+ levels in cardiac cells are coregulated by both ERs and βARs. Numerous studies provide compelling evidence that oestrogen influences the expression levels of Ca 2+ ‐handling proteins, whose functions are primarily under the regulation of βARs (Figure ) . In addition to the major proteins LTCC, RyR, PLB, SERCA and NCX, sarcolipin (SLN), an inhibitor of SERCA, plays a role in cardiac Ca 2+ handling .…”

Takotsubo Syndrome Therapy: Current Status and Future Directions

“…25,55 These conclusions have been strengthened further from the findings of Willis et al, who demonstrated in an animal model the contractile dysfunction in TTS is a consequence of mitochondrial impairment, with decreased ATP synthesis capacity and increased reactive oxygen species (ROS) production. 56 However, these metabolic derangements and energetics impairment also occur in heart failure irrespective of the disease etiology and what remains to be known how exactly the metabolic derangement in TTS is different from the conventional heart failure.…”