Mitochondrial Oxidative Stress Mediates Angiotensin II–Induced Cardiac Hypertrophy and Gαq Overexpression–Induced Heart Failure

Abstract

Rationale Mitochondrial dysfunction has been implicated in several cardiovascular diseases; however, the roles of mitochondrial oxidative stress and DNA damage in hypertensive cardiomyopathy are not well understood. Objective We evaluated the contribution of mitochondrial reactive oxygen species (ROS) to cardiac hypertrophy and failure by using genetic mouse models overexpressing catalase targeted to mitochondria and to peroxisomes. Methods and Results Angiotensin II increases mitochondrial ROS in cardiomyocytes, concomitant with increased mitochondrial protein carbonyls, mitochondrial DNA deletions, increased autophagy and signaling for mitochondrial biogenesis in hearts of Angiotensin II treated mice. The causal role of mitochondrial ROS in Angiotensin II-induced cardiomyopathy is shown by the observation that mice that overexpress catalase targeted to mitochondria, but not mice that overexpress wild-type peroxisomal catalase, are resistant to cardiac hypertrophy, fibrosis and mitochondrial damage induced by Angiotensin II, as well as heart failure induced by overexpression of Gαq. Furthermore, primary damage to mitochondrial DNA, induced by zidovudine administration or homozygous mutation of mitochondrial polymerase gamma, is also shown to contribute directly to the development of cardiac hypertrophy, fibrosis and failure. Conclusions These data indicate the critical role of mitochondrial ROS in cardiac hypertrophy and failure and support the potential use of mitochondrial-targeted antioxidants for prevention and treatment of hypertensive cardiomyopathy.

Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart

“…There are many reasons why a human heart can fail, but the available evidence suggests that a functional decline of mitochondria is one of the major mechanisms underlying heart failure progression [2][3][4] . Impaired mitochondria provoke energy-generation defects, the increased production of harmful reactive oxygen species (ROS), and a greater propensity to trigger apoptosis 5 .…”

Telomeres and Telomerase in The Aging Heart

“…(120) Mechanisms may include mitochondrial biogenesis that does not keep up with the increasing demand (121), mitochondrial uncoupling and decreased substrate availability, (122) and increased mitochondrial DNA deletions. (123) Studies have demonstrated that telomere dysfunctionactivated p53 directly leads to mitochondrial and metabolic compromise through the repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1a and PGC-1b. (53) PGC repression is associated with a profound compromise in mitochondrial biogenesis and function and subsequent decline in ATP generation, indicating that a fundamental problem of energy maintenance drives the aging process.…”

Free Radicals and Biomarkers Related to the Diagnosis of Cardiorenal Syndrome

“…NADPH oxidase activated by Ang II is the primary source of ROS that produces mitochondrial dysfunction [140]. The effects are due to both NOX4 and NOX2, which are upregulated by Ang II in a mitochondrial ROS-independent and dependent manner, respectively [141].…”