Genetic Inhibition of Mitochondrial Permeability Transition Pore Exacerbates Ryanodine Receptor 2 Dysfunction in Arrhythmic Disease.

The brief opening mode of the mitochondrial permeability transition pore (mPTP) serves as a calcium (Ca2+) release valve to prevent mitochondrial Ca2+ (mCa2+) overload. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to mutations in the Ca2+ release channel complex of ryanodine receptor 2 (RyR2). We hypothesize that inhibiting the mPTP opening in CPVT exacerbates the disease phenotype. By crossbreeding a CPVT model of CASQ2 knockout (KO) with a mouse missing CypD, an activator of mPTP, a double KO model (DKO) was generated. Echocardiography, cardiac histology, and live-cell imaging were employed to assess the severity of cardiac pathology. Western blot and RNAseq were performed to evaluate the contribution of various signaling pathways. Although exacerbated arrhythmias were reported, the DKO model did not exhibit pathological remodeling. Myocyte Ca2+ handling was similar to that of the CASQ2 KO mouse at a low pacing frequency. However, increased ROS production, activation of the CaMKII pathway, and hyperphosphorylation of RyR2 were detected in DKO. Transcriptome analysis identified altered gene expression profiles associated with electrical instability in DKO. Our study provides evidence that genetic inhibition of mPTP exacerbates RyR2 dysfunction in CPVT by increasing activation of the CaMKII pathway and subsequent hyperphosphorylation of RyR2.

HIV-1 Tat Upregulates the Receptor for Advanced Glycation End Products and Superoxide Dismutase-2 in the Heart of Transgenic Mice.

Cardiovascular disorder (CVD) is a common comorbidity in people living with HIV (PLWH). Although the underlying mechanisms are unknown, virotoxic HIV proteins, such as the trans-activator of transcription (Tat), likely contribute to CVD pathogenesis. Tat expression in mouse myocardium has been found to induce cardiac dysfunction and increase markers of endothelial toxicity. However, the role that Tat may play in the development of CVD pathogenesis is unclear. The capacity for Tat to impact cardiac function was assessed using AC16 human cardiomyocyte cells and adult male and female transgenic mice that conditionally expressed Tat [Tat(+)], or did not [Tat(-)]. In AC16 cardiomyocytes, Tat increased intracellular calcium. In Tat(+) mice, Tat expression was detected in both atrial and ventricular heart tissue. Tat(+) mice demonstrated an increased expression of the receptor for advanced glycation end products and superoxide dismutase-2 (SOD-2) in ventricular tissues compared to Tat(-) controls. No changes in SOD-1 or α-smooth muscle actin were observed. Despite Tat-mediated changes at the cellular level, no changes in echocardiographic measures were detected. Tat(+) mice had a greater proportion of ventricular mast cells and collagen; however, doxycycline exposure offset the latter effect. These data suggest that Tat exposure promotes cellular changes that can precede progression to CVD.