iNOS contributes to heart failure with preserved ejection fraction through mitochondrial dysfunction and Akt S-nitrosylation

NADPH Oxidases in Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction

“…Since advanced age is a major risk factor for the development of HFpEF [ 2 , 103 ] and oxidative stress is a major contributor to the aging of the heart and other organs [ 32 , 68 , 104 ], it is notable that Nox4 protein levels increased with age in the heart [ 63 ] and treatment with a pharmacological NOX1/NOX4 inhibitor preserved cardiac function in aged mice [ 68 ]. More importantly perhaps, cardiac Nox4 protein levels were upregulated in a mouse model of HFpEF [ 30 ]. It is also noteworthy that NOX2 and NOX4 contribute to atrial oxidative stress and susceptibility to atrial fibrillation [ 54 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 ], a comorbidity that is present in roughly one third of patients with HFpEF that can result in chronic arrhythmogenicity that precipitates the progression of cardiac failure [ 113 , 114 , 115 , 116 , 117 ].…”

“…NOX2 is activated by pathological stimuli such as AngII, aldosterone, and pressure overload [ 37 , 57 , 71 ], enabling the rapid inducibility of superoxide production [ 37 , 57 , 71 , 91 ]. In contrast, NOX4 has constitutive basal oxidase activity but its expression levels are upregulated in the heart by cardiovascular stress, such as in response to AngII, adrenergic stimulation, pressure overload [ 38 , 62 , 63 , 64 , 65 ], or the high-fat diet and N ω -nitro-L-arginine (HFD/L-NAME) model of HFpEF [ 30 ]. NOX4 is predominantly localized at intracellular organelle membranes, including at mitochondria, the endoplasmic reticulum, and nuclear envelope [ 62 , 63 , 67 , 157 ].…”

“…Indeed, multiple studies have uncovered pathogenic roles for NO in HFpEF, mediated at least in part through protein S-nitrosylation that is upregulated in the myocardium of mouse models and human patients with HFpEF [ 7 , 169 ]. Most notably, inducible NOS (iNOS) is upregulated in cardiomyocytes and is required for cardiac hypertrophy, fibrosis, diastolic dysfunction, edema, mitochondrial abnormalities, and exercise intolerance in the HFD/L-NAME mouse model of HFpEF [ 7 , 30 ]. S-nitrosylation of the endoplasmic reticulum stress transducing protein, inositol-requiring enzyme 1𝛼 (IRE1𝛼), is induced in HFpEF and prevents the IRE1𝛼 -mediated mRNA splicing of its effector, X-box-binding protein 1 ( Xbp1 ), that is required for the ER stress response and cardiac adaptation [ 7 , 170 ].…”

“…Importantly, the loss of iNOS or cardiomyocyte-specific overexpression of spliced Xbp1 rescues cardiac and systemic HFpEF phenotypes in the HFD/L-NAME model [ 7 ], suggesting essential roles for the iNOS-dependent S-nitrosylation of IRE1𝛼 in HFpEF. Akt S-nitrosylation at Cys-224 is also induced by iNOS in response to HFD/L-NAME, resulting in the inhibition of cardioprotective Akt signaling by reducing Ser-473 phosphorylation [ 30 ]. Thus, the upregulation of iNOS in HFpEF cardiomyocytes initiates pathologic S-nitrosylation-regulated signaling.…”

“…However, enhanced nitrosative stress is emerging as a hallmark and defining feature of HFpEF myocardium that occurs largely as a consequence of the induction of iNOS and nNOS levels and activity in cardiac myocytes [ 1 , 7 , 169 ]. There is also evidence that nitrosative stress can promote NOX activity and redox signaling in HFpEF, as iNOS was required for the upregulation of cardiac Nox4 levels and mitochondrial oxidative stress in response to HFD/L-NAME [ 30 ]. Further investigation of NOX and NOS isoforms in diastolic dysfunction will shed light on nitroso-redox crosstalk and redox/nitrosative signaling mechanisms that participate in the onset and progression of HFpEF.…”